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Publications

Total: displaying 50 out of 150 results
  • Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-Tetrahydrofuran in a Pseudo-Symmetric Dipeptide Isostere

    July 16, 2020
    Author(s): Linah Rusere, Gordon J. Lockbaum, Mina Henes, Sook-Kyung Lee, Ean Spielvogel, Desaboini Nageswara Rao, Klajdi Kosovrasti, Ellen A. Nalivaika, Ronald Swanstrom, Nese Kurt Yilmaz, Celia A. Schiffer, Akb...
    Source: Journal of medicinal chemistry; This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © 2020 American Chemical S...
    The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C2-symmetric dipeptide isostere are described. A s...
  • Deciphering complex mechanisms of resistance and loss of potency through coupled molecular dynamics and machine learning

    June 09, 2020
    Author(s): Florian Leidner, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: bioRxiv; The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
    Drug resistance threatens many critical therapeutics through mutations in the drug target. The molecular mechanisms by which combinations of mutations, especially involving those distal from the act...
  • IgA MAb blocks SARS-CoV-2 Spike-ACE2 interaction providing mucosal immunity

    May 15, 2020
    Author(s): Ejemel Monir, Qi Li, Shurong Hou, Zachary Schiller, Aaron Wallace, Alla Amcheslavsky, Nese Kurt Yilmaz, Jacqueline R. Toomey, Ryan Schneider, Lisa Cavacini, Mark S. Klempner, Celia A. Schiffer, Yan Wa...
    Source: bioRxiv : the preprint server for biology; The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No...
    COVID-19 caused by SARS-CoV-2 has become a global pandemic requiring the development of interventions for the prevention or treatment to curtail mortality and morbidity. No vaccine to boost mucosal ...
  • CryoEM Structure of CtBP2 Confirms Tetrameric Architecture

    April 07, 2020
    Author(s): Anne M. Jecrois, M. Michael Dcona, Xiaovan Deng, Dipankar Bandyopadhyay, Steven R. Grossman, Celia A. Schiffer, William E. Royer
    Source: bioRxiv; The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
    C-terminal binding proteins 1 and 2 (CtBP1 and CtBP2) are transcriptional regulators that activate or repress many genes involved in cellular development, apoptosis and metastasis. CtBP proteins are...
  • Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors

    March 31, 2020
    Author(s): Ashley N. Matthew, Jacqueto Zephyr, Nageswara Rao Desaboini, Mina Henes, Wasih Kamran, Klajdi Kosovrasti, Adam Hedger, Gordon J. Lockbaum, Jennifer Timm, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: mBio; Copyright © 2020 Matthew et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
    Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the...
  • Optimizing the refinement of merohedrally twinned P61 HIV-1 protease-inhibitor cocrystal structures

    March 01, 2020
    Author(s): Gordon J. Lockbaum, Florian Leidner, William E. Royer, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Acta crystallographica. Section D, Structural biology
    Twinning is a crystal-growth anomaly in which protein monomers exist in different orientations but are related in a specific way, causing diffraction reflections to overlap. Twinning imposes additio...
  • Molecular and Structural Mechanism of Pan-Genotypic HCV NS3/4A Protease Inhibition by Glecaprevir

    February 21, 2020
    Author(s): Jennifer Timm, Klajdi Kosovrasti, Mina Henes, Florian Leidner, Shurong Hou, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: ACS chemical biology
    Hepatitis C virus, causative agent of chronic viral hepatitis, infects 71 million people worldwide and is divided into seven genotypes and multiple subtypes with sequence identities between 68 to 82...
  • Characterizing protein-ligand binding using atomistic simulation and machine learning: Application to drug resistance in HIV-1 protease

    December 26, 2019
    Author(s): Troy W. Whitfield, Debra A. Ragland, Konstantin B. Zeldovich, Celia A. Schiffer
    Source: Journal of Chemical Theory and Computation; Copyright © 2019 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of C...
    Over the past several decades, atomistic simulations of biomolecules, whether carried out using molecular dynamics or Monte Carlo techniques, have provided detailed insights into their function. Com...
  • APOBEC3s: DNA-editing human cytidine deaminases

    September 01, 2019
    Author(s): Tania V. Silvas, Celia A. Schiffer
    Source: Protein science : a publication of the Protein Society
    Nucleic acid editing enzymes are essential components of the human immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins. Among these enzymes are cytidine deamina...
  • Mechanism for APOBEC3G catalytic exclusion of RNA and non-substrate DNA

    August 22, 2019
    Author(s): William C. Solomon, Wazo Myint, Shurong Hou, Tapan Kanai, Rashmi Tripathi, Nese Kurt Yilmaz, Celia A. Schiffer, Hiroshi Matsuo
    Source: Nucleic acids research; Copyright The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creat...
    The potent antiretroviral protein APOBEC3G (A3G) specifically targets and deaminates deoxycytidine nucleotides, generating deoxyuridine, in single stranded DNA (ssDNA) intermediates produced during ...
  • HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2' Ligands to Optimize Hydrogen Bonding in the Substrate Envelope

    August 21, 2019
    Author(s): Linah N. Rusere, Gordon J. Lockbaum, Sook-Kyung Lee, Mina Henes, Klajdi Kosovrasti, Ean Spielvogel, Ellen A. Nalivaika, Ronald Swanstrom, Nese Kurt Yilmaz, Celia A. Schiffer, Akbar Ali
    Source: Journal of medicinal chemistry
    A structure-guided design strategy was used to improve the resistance profile of HIV-1 protease inhibitors by optimizing hydrogen bonding and van der Waals interactions with the protease while stayi...
  • Molecular Determinants of Epistasis in HIV-1 Protease: Elucidating the Interdependence of L89V and L90M Mutations in Resistance

    August 19, 2019
    Author(s): Mina Henes, Klajdi Kosovrasti, Gordon J. Lockbaum, Florian Leidner, Gily S. Nachum, Ellen A. Nalivaika, Daniel N. Bolon, Nese Kurt Yilmaz, Celia A. Schiffer, Troy W. Whitfield
    Source: Biochemistry
    Protease inhibitors have the highest potency among antiviral therapies against HIV-1 infections, yet the virus can evolve resistance. Darunavir (DRV), currently the most potent Food and Drug Adminis...
  • Target-Specific Prediction of Ligand Affinity with Structure-Based Interaction Fingerprints

    August 19, 2019
    Author(s): Florian Leidner, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Journal of chemical information and modeling
    Discovery and optimization of small molecule inhibitors as therapeutic drugs have immensely benefited from rational structure-based drug design. With recent advances in high-resolution structure det...
  • Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance

    August 13, 2019
    Author(s): Mina Henes, Gordon J. Lockbaum, Klajdi Kosovrasti, Florian Leidner, Gily S. Nachum, Ellen A. Nalivaika, Sook-Kyung Lee, Ean Spielvogel, Shuntai Zhou, Ronald Swanstrom, Daniel N. Bolon, Nese Kurt Yilma...
    Source: ACS chemical biology
    Drug resistance continues to be a growing global problem. The efficacy of small molecule inhibitors is threatened by pools of genetic diversity in all systems, including antibacterials, antifungals,...
  • Molecular and structural mechanism of pan-genotypic HCV NS3/4A protease inhibition by glecaprevir

    July 03, 2019
    Author(s): Jennifer Timm, Klajdi Kosovrasti, Mina Henes, Florian Leidner, Shurong Hou, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: bioRxiv; The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
    Hepatitis C virus (HCV), causative agent of chronic viral hepatitis, infects 71 million people worldwide and is divided into seven genotypes and multiple subtypes with sequence identities between 68...
  • NMR and MD studies combined to elucidate inhibitor and water interactions of HIV-1 protease and their modulations with resistance mutations

    July 01, 2019
    Author(s): Rieko Ishima, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Journal of biomolecular NMR
    Over the last two decades, both the sensitivity of NMR and the time scale of molecular dynamics (MD) simulation have increased tremendously and have advanced the field of protein dynamics. HIV-1 pro...
  • Constrained mutational sampling of amino acids in HIV-1 protease evolution

    February 04, 2019
    Author(s): Jeffrey I. Boucher, Troy W. Whitfield, Ann Dauphin, Gily S. Nachum, Carl Hollins III, Konstantin B. Zeldovich, Ronald Swanstrom, Celia A. Schiffer, Jeremy Luban, Daniel N. Bolon
    Source: Molecular biology and evolution
    The evolution of HIV-1 protein sequences should be governed by a combination of factors including nucleotide mutational probabilities, the genetic code, and fitness. The impact of these factors on p...
  • Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease

    December 16, 2018
    Author(s): Aysegul Ozen, Kuan-Hung Lin, Keith P. Romano, Davide Tavella, Alicia Newton, Christos J. Petropoulos, Wei Huang, Cihan Aydin, Celia A. Schiffer
    Source: bioRxiv; The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
    Hepatitis C virus rapidly evolves, conferring resistance to direct acting antivirals. While resistance via active site mutations in the viral NS3/4A protease has been well characterized, the mechani...
  • Structural Adaptation of Darunavir Analogs Against Primary Mutations in HIV-1 Protease

    December 13, 2018
    Author(s): Gordon J. Lockbaum, Florian Leidner, Linah N. Rusere, Mina Henes, Klajdi Kosovrasti, Gily S. Nachum, Ellen A. Nalivaika, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: ACS infectious diseases
    HIV-1 protease is one of the prime targets of agents used in antiretroviral therapy against HIV. However, under selective pressure of protease inhibitors, primary mutations at the active site weaken...
  • Structural analysis of the active site and DNA binding of human cytidine deaminase APOBEC3B

    November 20, 2018
    Author(s): Shurong Hou, Tania V. Silvas, Florian Leidner, Ellen A. Nalivaika, Hiroshi Matsuo, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Journal of chemical theory and computation; This document is the Accepted Manuscript version of a Published Work that appeared in final form in J Chem Theory Comput., copyright © American Chemical Soc...
    APOBEC3s proteins (A3s), a family of human cytidine deaminases, protect the host from endogenous retro-elements and exogenous viral infections by introducing hypermutations. However, overexpressed A...
  • HIV-1 Protease Uses Bi-Specific S2/S2' Subsites to Optimize Cleavage of Two Classes of Target Sites

    November 07, 2018
    Author(s): Marc Potempa, Sook-Kyung Lee, Nese Kurt Yilmaz, Ellen A. Nalivaika, Amy Rogers, Ean Spielvogel, Charles W. Carter Jr., Celia A. Schiffer, Ronald Swanstrom
    Source: Journal of molecular biology
    Retroviral proteases (PRs) have a unique specificity that allows cleavage of sites with or without a P1' proline. A P1' proline is required at the MA/CA cleavage site due to its role in a post-cleav...
  • Mutations in influenza A virus neuraminidase and hemagglutinin confer resistance against a broadly neutralizing hemagglutinin stem antibody

    October 31, 2018
    Author(s): Kristina L. Prachanronarong, Aneth S. Canale, Ping Liu, Mohan Somasundaran, Shurong Hou, Yu-Ping Poh, Thomas Han, Quan Zhu, Nicholas Renzette, Konstantin B. Zeldovich, Timothy F. Kowalik, Nese Kurt Yi...
    Source: Journal of virology; Copyright © 2018, American Society for Microbiology. Accepted manuscript posted after 6 months as allowed by the publisher's author rights policy at https://journals.asm.org/cont...
    Influenza A virus (IAV), a major cause of human morbidity and mortality, continuously evolves in response to selective pressures. Stem-directed, broadly neutralizing antibodies (sBnAbs) targeting in...
  • A call to arms: Unifying the fight against resistance

    October 23, 2018
    Author(s): Alexis Kaushansky, Lizbeth Hedstrom, Aaron Goldman, Juswinder Singh, Priscilla L. Yang, Pradipsinh K. Rathod, Michael Cynamon, Dominik Wodarz, Daruka Mahadevan, Andrew Tomaras, Manuel A. Navia, Celia ...
    Source: Science Signaling
    This Editorial discusses the state of research on drug resistance in the fields of cancer, infectious disease, and agriculture. Reaching across the aisle for a more cross-collaborative approach may ...
  • Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3/4A Protease

    October 02, 2018
    Author(s): Ashley N. Matthew, Florian Leidner, Alicia Newton, Christos J. Petropoulos, Wei Huang, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Structure (London, England : 1993)
    Despite significant progress in hepatitis C virus (HCV) protease inhibitor (PI) drug design, resistance remains a problem causing treatment failure. Double-substitution variants, notably Y56H/D168A,...
  • T cell epitope engineering: an avian H7N9 influenza vaccine strategy for pandemic preparedness and response

    September 05, 2018
    Author(s): Leonard Moise, Bethany M. Biron, Christine M. Boyle, Nese Kurt Yilmaz, Hyesun Jang, Celia A. Schiffer, Ted M. Ross, William D. Martin, Anne S. De Groot
    Source: Human vaccines and immunotherapeutics; Copyright © 2018 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives Licens...
    The delayed availability of vaccine during the 2009 H1N1 influenza pandemic created a sense of urgency to better prepare for the next influenza pandemic. Advancements in manufacturing technology, sp...
  • Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA

    June 25, 2018
    Author(s): Atanu Maiti, Wazo Myint, Tapan Kanai, Krista Delviks-Frankenberry, Christina Sierra Rodriguez, Vinay K. Pathak, Celia A. Schiffer, Hiroshi Matsuo
    Source: Nature communications; © The Author(s) 2018. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution ...
    The human APOBEC3G protein is a cytidine deaminase that generates cytidine to deoxy-uridine mutations in single-stranded DNA (ssDNA), and capable of restricting replication of HIV-1 by generating mu...
  • Assembly of human C-terminal binding protein (CtBP) into tetramers

    June 08, 2018
    Author(s): Andrew G. Bellesis, Anne M. Jecrois, Janelle A. Hayes, Celia A. Schiffer, William E. Royer
    Source: The Journal of biological chemistry; © 2018 Bellesis et al. Publisher's PDF posted after 12 month embargo as allowed by publisher's copyright policy at http://www.jbc.org/site/misc/edpolicy.xhtml#copy...
    C-terminal binding protein 1 (CtBP1) and CtBP2 are transcriptional coregulators that repress numerous cellular processes, such as apoptosis, by binding transcription factors and recruiting chromatin...
  • Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants

    May 17, 2018
    Author(s): Linah Rusere, Ashley N. Matthew, Gordon J. Lockbaum, Muhammad Jahangir, Alicia Newton, Christos J. Petropoulos, Wei Huang, Nese Kurt Yilmaz, Celia A. Schiffer, Akbar Ali
    Source: ACS medicinal chemistry letters
    A series of linear HCV NS3/4A protease inhibitors was designed by eliminating the P2-P4 macrocyclic linker in grazoprevir, which, in addition to conferring conformational flexibility, allowed struct...
  • Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions

    May 14, 2018
    Author(s): Tania V. Silvas, Shurong Hou, Wazo Myint, Ellen A. Nalivaika, Mohan Somasundaran, Brian A. Kelch, Hiroshi Matsuo, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Scientific reports; © The Author(s) 2018. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and...
    The APOBEC3 (A3) family of human cytidine deaminases is renowned for providing a first line of defense against many exogenous and endogenous retroviruses. However, the ability of these proteins to d...
  • Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease

    May 08, 2018
    Author(s): Florian Leidner, Nese Kurt Yilmaz, Janet L. Paulsen, Yves A. Muller, Celia A. Schiffer
    Source: Journal of chemical theory and computation
    Water is essential in many biological processes, and the hydration structure plays a critical role in facilitating protein folding, dynamics, and ligand binding. A variety of biophysical spectroscop...
  • Synonymous Mutations at the Beginning of the Influenza A Virus Hemagglutinin Gene Impact Experimental Fitness

    April 13, 2018
    Author(s): Aneth S. Canale, Sergey V. Venev, Troy W. Whitfield, Daniel R. Caffrey, Wayne A. Marasco, Celia A. Schiffer, Timothy F. Kowalik, Jeffrey D. Jensen, Robert W. Finberg, Konstantin B. Zeldovich, Jennifer...
    Source: Journal of molecular biology
    The fitness effects of synonymous mutations can provide insights into biological and evolutionary mechanisms. We analyzed the experimental fitness effects of all single-nucleotide mutations, includi...
  • Probing Structural Changes among Analogous Inhibitor-Bound Forms of HIV-1 Protease and a Drug-Resistant Mutant in Solution by Nuclear Magnetic Resonance

    March 13, 2018
    Author(s): Shahid N. Khan, John D. Persons, Janet L. Paulsen, Michel Guerrero, Celia A. Schiffer, Nese Kurt Yilmaz, Rieko Ishima
    Source: Biochemistry
    In the era of state-of-the-art inhibitor design and high-resolution structural studies, detection of significant but small protein structural differences in the inhibitor-bound forms is critical to ...
  • Structural Determination of the Broadly Reactive Anti-IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope

    December 12, 2017
    Author(s): Yuval Avnir, Kristina L. Prachanronarong, Shurong Hou, Brendan J. Hilbert, Markus-Frederik Bohn, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang, Nese Kurt Yilmaz, Celia A. Schiffer, Wayne A. ...
    Source: Cell reports; Copyright 2017 The Authors. Open Access funded by the US Department of Defense (DoD) or performed by an employee of DoD. This is an open access article under the CC BY-NC-ND license (htt...
    The heavy chain IGHV1-69 germline gene exhibits a high level of polymorphism and shows biased use in protective antibody (Ab) responses to infections and vaccines. It is also highly expressed in sev...
  • Mavyret: A Pan-Genotypic Combination Therapy for the Treatment of Hepatitis C Infection - Published as part of the Biochemistry series "Biochemistry to Bedside"

    December 01, 2017
    Author(s): Ashley N. Matthew, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Biochemistry
  • CRISPR-Cas9-mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy

    October 31, 2017
    Author(s): Leyuan Ma, Jeffrey I. Boucher, Janet L. Paulsen, Sebastian Matuszewski, Christopher A. Eide, Jianhong Ou, Garrett Eickelberg, Richard D. Press, Lihua (Julie) Zhu, Brian J. Druker, Susan Branford, Scot...
    Source: Proceedings of the National Academy of Sciences of the United States of America
    Developing tools to accurately predict the clinical prevalence of drug-resistant mutations is a key step toward generating more effective therapeutics. Here we describe a high-throughput CRISPR-Cas9...
  • Elucidating the Interdependence of Drug Resistance from Combinations of Mutations

    September 15, 2017
    Author(s): Debra A. Ragland, Troy W. Whitfield, Sook-Kyung Lee, Ronald Swanstrom, Konstantin B. Zeldovich, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Journal of chemical theory and computation
    HIV-1 protease is responsible for the cleavage of 12 nonhomologous sites within the Gag and Gag-Pro-Pol polyproteins in the viral genome. Under the selective pressure of protease inhibition, the vir...
  • Citrullination of NF-kappaB p65 promotes its nuclear localization and TLR-induced expression of IL-1beta and TNFalpha

    June 09, 2017
    Author(s): Bo Sun, Nishant Dwivedi, Tyler J. Bechtel, Janet L. Paulsen, Aaron Muth, Mandar Bawadekar, Gang Li, Paul R. Thompson, Miriam A. Shelef, Celia A. Schiffer, Eranthie Weerapana, I-Cheng Ho
    Source: Science immunology
    Many citrullinated proteins are known autoantigens in rheumatoid arthritis, a disease mediated by inflammatory cytokines, such as tumor necrosis factor-alpha (TNFalpha). Citrullinated proteins are g...
  • Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants

    June 08, 2017
    Author(s): Ashley N. Matthew, Jacqueto Zephyr, Caitlin J. Hill, Muhammad Jahangir, Alicia Newton, Christos J. Petropoulos, Wei Huang, Nese Kurt Yilmaz, Celia A. Schiffer, Akbar Ali
    Source: Journal of medicinal chemistry
    A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinox...
  • Interdependence of Inhibitor Recognition in HIV-1 Protease

    May 09, 2017
    Author(s): Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Journal of chemical theory and computation; This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for n...
    Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recogn...
  • Dengue Virus NS2B/NS3 Protease Inhibitors Exploiting the Prime Side

    April 28, 2017
    Author(s): Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Journal of virology; Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.
    The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including...
  • Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity

    April 28, 2017
    Author(s): Takahide Kouno, Tania V. Silvas, Brendan J. Hilbert, Shivender Shandilya, Markus-Frederik Bohn, Brian A. Kelch, William E. Royer, Mohan Somasundaran, Nese Kurt Yilmaz, Hiroshi Matsuo, Celia A. Schiffe...
    Source: Nature communications; Copyright The Author(s) 2017.
    Nucleic acid editing enzymes are essential components of the immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins, and contribute to the diversification and leth...
  • Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase

    December 13, 2016
    Author(s): Kristina L. Prachanronarong, Aysegul Ozen, Kelly Thayer, L. Safak Yilmaz, Konstantin B. Zeldovich, Daniel N. Bolon, Timothy F. Kowalik, Jeffrey D. Jensen, Robert W. Finberg, Jennifer P. Wang, Nese Kur...
    Source: Journal of chemical theory and computation
    Neuraminidase (NA) inhibitors are used for the prevention and treatment of influenza A virus infections. Two subtypes of NA, N1 and N2, predominate in viruses that infect humans, but differential pa...
  • Structural and molecular analysis of a protective epitope of Lyme disease antigen OspA and antibody interactions

    November 16, 2016
    Author(s): Shivender Shandilya, Nese Kurt Yilmaz, Andrew Sadowski, Ejemel Monir, Zachary A. Schiller, William D. Thomas Jr., Mark S. Klempner, Celia A. Schiffer, Yang Wang
    Source: Journal of molecular recognition : JMR
    The murine monoclonal antibody LA-2 recognizes a clinically protective epitope on outer surface protein (OspA) of Borrelia burgdorferi, the causative agent of Lyme disease in North America. Human an...
  • Dengue Protease Substrate Recognition: Binding of the Prime Side

    October 14, 2016
    Author(s): Kuan-Hung Lin, Ellen A. Nalivaika, Kristina L. Prachanronarong, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: ACS infectious diseases
    Dengue virus (DENV), transmitted predominantly in tropical and subtropical regions by the mosquito Aedes aegypti, infects millions of people and leads to dengue fever and thousands of deaths each ye...
  • Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease

    September 14, 2016
    Author(s): Djade I. Soumana, Nese Kurt Yilmaz, Akbar Ali, Kristina L. Prachanronarong, Celia A. Schiffer
    Source: Journal of the American Chemical Society
    Hepatitis C virus (HCV), affecting an estimated 150 million people worldwide, is the leading cause of viral hepatitis, cirrhosis and hepatocellular carcinoma. HCV is genetically diverse with six gen...
  • Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172

    April 15, 2016
    Author(s): Djade I. Soumana, Nese Kurt Yilmaz, Kristina L. Prachanronarong, Cihan Aydin, Akbar Ali, Celia A. Schiffer
    Source: ACS chemical biology
    Recent advances in direct-acting antivirals against Hepatitis C Virus (HCV) have led to the development of potent inhibitors, including MK-5172, that target the viral NS3/4A protease with relatively...
  • Improving Viral Protease Inhibitors to Counter Drug Resistance

    April 15, 2016
    Author(s): Nese Kurt Yilmaz, Ronald I. Swanstrom, Celia A. Schiffer
    Source: Trends in microbiology
    Drug resistance is a major problem in health care, undermining therapy outcomes and necessitating novel approaches to drug design. Extensive studies on resistance to viral protease inhibitors, parti...
  • A Balance between Inhibitor Binding and Substrate Processing Confers Influenza Drug Resistance

    February 13, 2016
    Author(s): Li Jiang, Ping Liu, Claudia Bank, Nicholas Renzette, Kristina L. Prachanronarong, L. Safak Yilmaz, Daniel R. Caffrey, Konstantin B. Zeldovich, Celia A. Schiffer, Timothy F. Kowalik, Jeffrey D. Jensen,...
    Source: Journal of molecular biology
    The therapeutic benefits of the neuraminidase (NA) inhibitor oseltamivir are dampened by the emergence of drug resistance mutations in influenza A virus (IAV). To investigate the mechanistic feature...
  • Inhibition of APOBEC3G activity impedes double-stranded DNA repair

    January 01, 2016
    Author(s): Ponnandy Prabhu, Shivender Shandilya, Elena Britan-Rosich, Adi Nagler, Celia A. Schiffer, Moshe Kotler
    Source: The FEBS journal
    The cellular cytidine deaminase APOBEC3G (A3G) was first described as an anti-HIV-1 restriction factor, acting by directly deaminating reverse transcripts of the viral genome. HIV-1 Vif neutralizes ...
  • Modulation of HIV protease flexibility by the T80N mutation

    November 01, 2015
    Author(s): Hao Zhou, Shangyang Li, John Badger, Ellen A. Nalivaika, Yufeng Cai, Jennifer E. Foulkes-Murzycki, Celia A. Schiffer, Lee Makowski
    Source: Proteins
    The flexibility of HIV protease (HIVp) plays a critical role in enabling enzymatic activity and is required for substrate access to the active site. While the importance of flexibility in the flaps ...
  • Simultaneously Targeting the NS3 Protease and Helicase Activities for More Effective Hepatitis C Virus Therapy

    August 21, 2015
    Author(s): Jean Ndjomou, M Josie. Corby, Noreena L. Sweeney, Alicia M. Hanson, Cihan Aydin, Akbar Ali, Celia A. Schiffer, Kelin Li, Kevin J. Frankowski, Frank J. Schoenen, David N. Frick
    Source: ACS chemical biology
    This study examines the specificity and mechanism of action of a recently reported hepatitis C virus (HCV) nonstructural protein 3 (NS3) helicase-protease inhibitor (HPI), and the interaction of HPI...
  • A Direct Interaction with RNA Dramatically Enhances the Catalytic Activity of the HIV-1 Protease In Vitro

    July 17, 2015
    Author(s): Marc Potempa, Ellen A. Nalivaika, Debra A. Ragland, Sook-Kyung Lee, Celia A. Schiffer, Ronald Swanstrom
    Source: Journal of molecular biology
    Though the steps of human immunodeficiency virus type 1 (HIV-1) virion maturation are well documented, the mechanisms regulating the proteolysis of the Gag and Gag-Pro-Pol polyproteins by the HIV-1 ...
  • Structural basis for mutation-induced destabilization of profilin 1 in ALS

    June 30, 2015
    Author(s): Sivakumar Boopathy, Tania V. Silvas, Maeve Tischbein, Silvia Jansen, Shivender Shandilya, Jill A. Zitzewitz, John E. Landers, Bruce L. Goode, Celia A. Schiffer, Daryl A. Bosco
    Source: Proceedings of the National Academy of Sciences of the United States of America; Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq...
    Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked m...
  • Structure of the Vif-binding domain of the antiviral enzyme APOBEC3G

    June 01, 2015
    Author(s): Takahide Kouno, Elizabeth M. Luengas, Megumi Shigematsu, Shivender Shandilya, JingYing Zhang, Luan Chen, Mayuko Hara, Celia A. Schiffer, Reuben S. Harris, Hiroshi Matsuo
    Source: Nature structural and molecular biology
    The human APOBEC3G (A3G) DNA cytosine deaminase restricts and hypermutates DNA-based parasites including HIV-1. The viral infectivity factor (Vif) prevents restriction by triggering A3G degradation....
  • The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization

    May 05, 2015
    Author(s): Markus-Frederik Bohn, Shivender Shandilya, Tania V. Silvas, Ellen A. Nalivaika, Takahide Kouno, Brian Kelch, Sean P. Ryder, Nese Kurt Yilmaz, Mohan Somasundaran, Celia A. Schiffer
    Source: Structure (London, England : 1993)
    Deaminase activity mediated by the human APOBEC3 family of proteins contributes to genomic instability and cancer. APOBEC3A is by far the most active in this family and can cause rapid cell death wh...
  • REdiii: a pipeline for automated structure solution

    May 01, 2015
    Author(s): Markus-Frederik Bohn, Celia A. Schiffer
    Source: Acta crystallographica. Section D, Biological crystallography; Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.iucr.org/services/authorrights.html
    High-throughput crystallographic approaches require integrated software solutions to minimize the need for manual effort. REdiii is a system that allows fully automated crystallographic structure so...
  • Structure-Guided Design of a High Affinity Inhibitor to Human CtBP

    April 17, 2015
    Author(s): Brendan J. Hilbert, Benjamin L. Morris, Keith C. Ellis, Janet L. Paulsen, Celia A. Schiffer, Steven R. Grossman, William E. Royer
    Source: ACS chemical biology
    Oncogenic transcriptional coregulators C-terminal Binding Protein (CtBP) 1 and 2 possess regulatory d-isomer specific 2-hydroxyacid dehydrogenase (D2-HDH) domains that provide an attractive target f...
  • Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment

    February 23, 2015
    Author(s): Konstantin B. Zeldovich, Ping Liu, Nicholas Renzette, Matthieu Foll, Serena T. Pham, Sergey V. Venev, Glen R. Gallagher, Daniel N. Bolon, Evelyn A. Kurt-Jones, Jeffrey D. Jensen, Daniel R. Caffrey, Ce...
    Source: Molecular biology and evolution
    Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cro...
  • Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution

    February 01, 2015
    Author(s): Nevra Ozer, Aysegul Ozen, Celia A. Schiffer, Turkan Haliloglu
    Source: Evolutionary applications; Copyright © 2014 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in...
    Drug resistance is caused by mutations that change the balance of recognition favoring substrate cleavage over inhibitor binding. Here, a structural dynamics perspective of the regained wild-type fu...
  • A computational analysis of the structural determinants of APOBEC3's catalytic activity and vulnerability to HIV-1 Vif

    December 01, 2014
    Author(s): Shivender Shandilya, Markus-Frederik Bohn, Celia A. Schiffer
    Source: Virology
    APOBEC3s (A3) are Zn(2+) dependent cytidine deaminases with diverse biological functions and implications for cancer and immunity. Four of the seven human A3s restrict HIV by 'hypermutating' the rev...
  • Structural analysis of asunaprevir resistance in HCV NS3/4A protease

    November 21, 2014
    Author(s): Djade Soumana, Akbar Ali, Celia A. Schiffer
    Source: ACS chemical biology
    Asunaprevir (ASV), an isoquinoline-based competitive inhibitor targeting the hepatitis C virus (HCV) NS3/4A protease, is very potent in vivo. However, the potency is significantly compromised by the...
  • Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease

    November 11, 2014
    Author(s): Aysegul Ozen, Kuan-Hung Lin, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Proceedings of the National Academy of Sciences of the United States of America
    Drug resistance mutations in response to HIV-1 protease inhibitors are selected not only in the drug target but elsewhere in the viral genome, especially at the protease cleavage sites in the precur...
  • Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease

    August 27, 2014
    Author(s): Debra A. Ragland, Ellen A. Nalivaika, Madhavi N. L. Nalam, Kristina L. Prachanronarong, Hong Cao, Rajintha M. Bandaranayake, Yufeng Cai, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Journal of the American Chemical Society
    HIV-1 protease inhibitors are part of the highly active antiretroviral therapy effectively used in the treatment of HIV infection and AIDS. Darunavir (DRV) is the most potent of these inhibitors, so...
  • Drug Resistance Mutations Alter Dynamics of Inhibitor-Bound HIV-1 Protease

    August 12, 2014
    Author(s): Yufeng Cai, Wazo Myint, Janet L. Paulsen, Celia A. Schiffer, Rieko Ishima, Nese Kurt Yilmaz
    Source: Journal of chemical theory and computation
    Under the selective pressure of therapy, HIV-1 protease mutants resistant to inhibitors evolve to confer drug resistance. Such mutations can impact both the dynamics and structures of the bound and ...
  • HIV-1 protease-substrate coevolution in nelfinavir resistance

    July 01, 2014
    Author(s): Madhavi Kolli, Aysegul Ozen, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Journal of virology; Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.
    Resistance to various human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. The vi...
  • MassTERi: Promoting Translational Research and Entrepreneurship at the University of Massachusetts Medical School

    May 20, 2014
    Author(s): Melissa J. Moore, Celia A. Schiffer, Anastasia Khvorova, Anita Ballesteros, Cynthia Fuhrmann, Jean A. King, Margaret Koziel, Thomas McCullough, Linda Plano
    Source: UMass Center for Clinical and Translational Science Research Retreat; Copyright the Author(s)
    MassTERi is a faculty-led initiative to foster entrepreneurship among UMass Medical School students, postdocs and faculty, and facilitate translation of UMMS discoveries into drugs, products, techno...
  • Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design

    May 02, 2014
    Author(s): Brendan J. Hilbert, Steven R. Grossman, Celia A. Schiffer, William E. Royer
    Source: FEBS letters
    The oncogenic corepressors C-terminal Binding Protein (CtBP) 1 and 2 harbor regulatory d-isomer specific 2-hydroxyacid dehydrogenase (d2-HDH) domains. 4-Methylthio 2-oxobutyric acid (MTOB) exhibits ...
  • Influenza virus drug resistance: a time-sampled population genetics perspective

    February 27, 2014
    Author(s): Matthieu Foll, Yu Ping Poh, Nicholas Renzette, Anna Ferrer Admetlla, Claudia Bank, Hyunjin Shim, Anna Sapfo Malaspinas, Gregory Ewing, Ping Liu, Daniel Wegmann, Daniel R. Caffrey, Konstantin B. Zeldov...
    Source: PLoS genetics; © 2014 Foll et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction...
    The challenge of distinguishing genetic drift from selection remains a central focus of population genetics. Time-sampled data may provide a powerful tool for distinguishing these processes, and we ...
  • Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro

    January 01, 2014
    Author(s): Nicholas Renzette, Daniel R. Caffrey, Konstantin B. Zeldovich, Ping Liu, Glen R. Gallagher, Daniel Aiello, Alyssa J. Porter, Evelyn A. Kurt-Jones, Daniel N. Bolon, Yu-Ping Poh, Jeffrey D. Jensen, Celi...
    Source: Journal of virology; Copyright © 2014, American Society for Microbiology. All Rights Reserved. Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/m...
    Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, a neuraminidase inhibitor that prevents the release of nasc...
  • Improving the Resistance Profile of Hepatitis C NS3/4A Inhibitors: Dynamic Substrate Envelope Guided Design

    December 10, 2013
    Author(s): Aysegul Ozen, Woody Sherman, Celia A. Schiffer
    Source: Journal of chemical theory and computation
    Drug resistance is a principal concern in the treatment of quickly evolving diseases. The viral protease NS3/4A is a primary drug target for the hepatitis C virus (HCV) and is known to evolve resist...
  • Development of a Novel Screening Strategy Designed to Discover a New Class of HIV Drugs

    December 04, 2013
    Author(s): Nancy Cheng, Sook-Kyung Lee, P. Scott Donover, Mel Reichman, Celia A. Schiffer, Emily A. Hull-Ryde, Ronald I. Swanstrom, William P. Janzen
    Source: Journal of laboratory automation
    Current antiretroviral treatments target multiple pathways important for human immunodeficiency virus (HIV) multiplication, including viral entry, synthesis and integration of the DNA provirus, and ...
  • Testing the substrate-envelope hypothesis with designed pairs of compounds

    November 15, 2013
    Author(s): Yang Shen, Michael D. Altman, Akbar Ali, Madhavi N. L. Nalam, Hong Cao, Tariq M. Rana, Celia A. Schiffer, Bruce Tidor
    Source: ACS chemical biology
    Acquired resistance to therapeutic agents is a significant barrier to the development of clinically effective treatments for diseases in which evolution occurs on clinical time scales, frequently ar...
  • Efficient Computation of Small-Molecule Configurational Binding Entropy and Free Energy Changes by Ensemble Enumeration

    November 12, 2013
    Author(s): Nathaniel W. Silver, Bracken M. King, Madhavi N. L. Nalam, Hong Cao, Akbar Ali, G. S. Kiran Kumar Reddy, Tariq M. Rana, Celia A. Schiffer, Bruce Tidor
    Source: Journal of chemical theory and computation
    Here we present a novel, end-point method using the dead-end-elimination and A* algorithms to efficiently and accurately calculate the change in free energy, enthalpy, and configurational entropy of...
  • The interdomain interface in bifunctional enzyme protein 3/4A (NS3/4A) regulates protease and helicase activities

    October 19, 2013
    Author(s): Cihan Aydin, Sourav Mukherjee, Alicia M. Hanson, David N. Frick, Celia A. Schiffer
    Source: Protein science : a publication of the Protein Society
    Hepatitis C (HCV) protein 3/4A (NS3/4A) is a bifunctional enzyme comprising two separate domains with protease and helicase activities, which are essential for viral propagation. Both domains are st...
  • Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance

    September 19, 2013
    Author(s): Madhavi N. L. Nalam, Akbar Ali, G. S. Kiran Kumar Reddy, Hong Cao, Saima G. Anjum, Michael D. Altman, Nese Kurt Yilmaz, Bruce Tidor, Tariq M. Rana, Celia A. Schiffer
    Source: Chemistry and biology
    The rapid evolution of HIV under selective drug pressure has led to multidrug resistant (MDR) strains that evade standard therapies. We designed highly potent HIV-1 protease inhibitors (PIs) using t...
  • A sensitive assay using a native protein substrate for screening HIV-1 maturation inhibitors targeting the protease cleavage site between the matrix and capsid

    July 23, 2013
    Author(s): Sook-Kyung Lee, Nancy Cheng, Emily A. Hull-Ryde, Marc Potempa, Celia A. Schiffer, William P. Janzen, Ronald I. Swanstrom
    Source: Biochemistry
    The matrix/capsid processing site in the HIV-1 Gag precursor is likely the most sensitive target to inhibit HIV-1 replication. We have previously shown that modest incomplete processing at the site ...
  • Evaluating the Role of Macrocycles in the Susceptibility of Hepatitis C Virus NS3/4A Protease Inhibitors to Drug Resistance

    July 19, 2013
    Author(s): Akbar Ali, Cihan Aydin, Reinhold Gildemeister, Keith P. Romano, Hong Cao, Aysegul Ozen, Djade Soumana, Alicia Newton, Christos J. Petropoulos, Wei Huang, Celia A. Schiffer
    Source: ACS chemical biology
    The hepatitis C virus (HCV) infects an estimated 150 million people worldwide and is the major cause of viral hepatitis, cirrhosis, and liver cancer. The available antiviral therapies, which include...
  • Interview with Celia Schiffer

    July 01, 2013
    Author(s): Celia A. Schiffer
    Source: Future medicinal chemistry
    Celia Schiffer, a Professor in Biochemistry and Molecular Pharmacology; a former Director of UMass Center for AIDS Research; and a Founder and Co-Director for the Institute for Drug Resistance (Univ...
  • Prototypical Recombinant Multi-Protease Inhibitor Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type-1

    June 24, 2013
    Author(s): Vici Varghese, Yumi Mitsuya, W. Jeffrey Fessel, Tommy F. Liu, George L. Melikian, David A. Katzenstein, Celia A. Schiffer, Susan P. Holmes, Robert W. Shafer
    Source: Antimicrobial agents and chemotherapy
    The many genetic manifestations of HIV-1 protease inhibitor (PI) resistance present challenges to research into the mechanisms of PI-resistance and the assessment of new PIs. To address these challe...
  • Crystal Structure of the DNA Cytosine Deaminase APOBEC3F: The Catalytically Active and HIV-1 Vif-Binding Domain

    June 04, 2013
    Author(s): Markus-Frederik Bohn, Shivender M. D. Shandilya, John S. Albin, Takahide Kouno, Brett D. Anderson, Rebecca M. McDougle, Michael A. Carpenter, Anurag Rathore, Leah Evans, Ahkillah N. Davis, JingYing Zh...
    Source: Structure (London, England : 1993)
    Human APOBEC3F is an antiretroviral single-strand DNA cytosine deaminase, susceptible to degradation by the HIV-1 protein Vif. In this study the crystal structure of the HIV Vif binding, catalytical...
  • Structural and thermodynamic basis of amprenavir/darunavir and atazanavir resistance in HIV-1 protease with mutations at residue 50

    April 01, 2013
    Author(s): Seema Mittal, Rajintha M. Bandaranayake, Nancy M. King, Moses Prabu-Jeyabalan, Madhavi N. L. Nalam, Ellen A. Nalivaika, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: Journal of virology
    Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such sub...
  • Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease

    March 15, 2013
    Author(s): Jennifer E. Foulkes-Murzycki, Christina Rosi, Nese Kurt Yilmaz, Robert W. Shafer, Celia A. Schiffer
    Source: ACS chemical biology
    Understanding the interdependence of multiple mutations in conferring drug resistance is crucial to the development of novel and robust inhibitors. As HIV-1 protease continues to adapt and evade inh...
  • Methyl- and Normal-Cytosine Deamination by the Foreign DNA Restriction Enzyme APOBEC3A

    October 05, 2012
    Author(s): Michael A. Carpenter, Ming Li, Anurag Rathore, Lela Lackey, Emily R. Law, Allison M. Land, Brandon Leonard, Shivender M. D. Shandilya, Markus-Frederik Bohn, Celia A. Schiffer, William L. Brown, Reuben...
    Source: The Journal of biological chemistry
    Multiple studies have indicated that the TET oxidases and, more controversially, the AID/APOBEC deaminases have the capacity to convert genomic DNA 5-methylcytosine (MeC) into altered nucleobases th...
  • Extreme Entropy-Enthalpy Compensation in a Drug-Resistant Variant of HIV-1 Protease

    September 21, 2012
    Author(s): Nancy M. King, Moses Prabu-Jeyabalan, Rajintha M. Bandaranayake, Madhavi N. L. Nalam, Ellen A. Nalivaika, Aysegul Ozen, Turkan Haliloglu, Nese Kurt Yilmaz, Celia A. Schiffer
    Source: ACS chemical biology
    The development of HIV-1 protease inhibitors has been the historic paradigm of rational structure-based drug design, where structural and thermodynamic analyses have assisted in the discovery of nov...
  • Structural insights into neuronal K+ channel-calmodulin complexes

    August 21, 2012
    Author(s): Karen Mruk, Shivender Shandilya, Robert O. Blaustein, Celia A. Schiffer, William R. Kobertz
    Source: Proceedings of the National Academy of Sciences of the United States of America
    Calmodulin (CaM) is a ubiquitous intracellular calcium sensor that directly binds to and modulates a wide variety of ion channels. Despite the large repository of high-resolution structures of CaM b...
  • The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors

    July 26, 2012
    Author(s): Keith P. Romano, Akbar Ali, Cihan Aydin, Djade Soumana, Aysegul Ozen, Laura M. Deveau, Casey Silver, Hong Cao, Alicia Newton, Christos J. Petropoulos, Wei Huang, Celia A. Schiffer
    Source: PLoS pathogens; Copyright: © 2012 Romano et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, an...
    Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therap...
  • Design, synthesis, and biological and structural evaluations of novel HIV-1 protease inhibitors to combat drug resistance

    July 26, 2012
    Author(s): Maloy Kumar Parai, David J. Huggins, Hong Cao, Madhavi N. L. Nalam, Akbar Ali, Celia A. Schiffer, Bruce Tidor, Tariq M. Rana
    Source: Journal of medicinal chemistry
    A series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate-envelope constraints. The PIs incorporate var...
  • Mass spectrometry tools for analysis of intermolecular interactions

    July 24, 2012
    Author(s): Jared R. Auclair, Mohan Somasundaran, Karin M. Green, James E. Evans, Celia A. Schiffer, Dagmar Ringe, Gregory A. Petsko, Jeffrey N. Agar
    Source: Methods in molecular biology (Clifton, N.J.)
    The small quantities of protein required for mass spectrometry (MS) make it a powerful tool to detect binding (protein-protein, protein-small molecule, etc.) of proteins that are difficult to expres...
  • Structural, kinetic, and thermodynamic studies of specificity designed HIV-1 protease

    July 01, 2012
    Author(s): Oscar Alvizo, Seema Mittal, Stephen L. Mayo, Celia A. Schiffer
    Source: Protein science : a publication of the Protein Society
    HIV-1 protease recognizes and cleaves more than 12 different substrates leading to viral maturation. While these substrates share no conserved motif, they are specifically selected for and cleaved b...
  • Quantitative comparison of errors in 15N transverse relaxation rates measured using various CPMG phasing schemes

    May 01, 2012
    Author(s): Wazo Myint, Yufeng Cai, Celia A. Schiffer, Rieko Ishima
    Source: Journal of biomolecular NMR
    Nitrogen-15 Carr-Purcell-Meiboom-Gill (CPMG) transverse relaxation experiment are widely used to characterize protein backbone dynamics and chemical exchange parameters. Although an accurate value o...
  • Context surrounding processing sites is crucial in determining cleavage rate of a subset of processing sites in HIV-1 Gag and Gag-Pro-Pol polyprotein precursors by viral protease

    April 13, 2012
    Author(s): Sook-Kyung Lee, Marc Potempa, Madhavi Kolli, Aysegul Ozen, Celia A. Schiffer, Ronald I. Swanstrom
    Source: The Journal of biological chemistry
    Processing of the human immunodeficiency virus type 1 (HIV-1) Gag and Gag-Pro-Pol polyproteins by the HIV-1 protease (PR) is essential for the production of infectious particles. However, the determ...
  • First-in-class small molecule inhibitors of the single-strand DNA cytosine deaminase APOBEC3G

    March 16, 2012
    Author(s): Ming Li, Shivender Shandilya, Michael A. Carpenter, Anurag Rathore, William L. Brown, Angela L. Perkins, Daniel A. Harki, Jonathan Solberg, Derek J. Hook, Krishan K. Pandey, Michael A. Parniak, Jeffre...
    Source: ACS Chem Biol
    APOBEC3G is a single-stranded DNA cytosine deaminase that comprises part of the innate immune response to viruses and transposons. Although APOBEC3G is the prototype for understanding the larger mam...
  • Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease

    March 07, 2012
    Author(s): Seema Mittal, Yufeng Cai, Madhavi N. L. Nalam, Daniel N. A. Bolon, Celia A. Schiffer
    Source: Journal of the American Chemical Society
    Human immunodeficiency virus Type-1 (HIV-1) protease is crucial for viral maturation and infectivity. Studies of protease dynamics suggest that the rearrangement of the hydrophobic core is essential...
  • TMC310911, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, Shows In Vitro an Improved Resistance Profile and Higher Genetic Barrier to Resistance Compared with Current Protease Inhibitors

    December 08, 2011
    Author(s): Inge Dierynck, Herwig Van Marck, Marcia Van Ginderen, Tim H. M. Jonckers, Madhavi N. L. Nalam, Celia A. Schiffer, Araz Raoof, Guenter Kraus, Gaston Picchio
    Source: Antimicrobial agents and chemotherapy
    TMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has ...
  • The challenge of developing robust drugs to overcome resistance

    September 26, 2011
    Author(s): Amy C. Anderson, Michael P. Pollastri, Celia A. Schiffer, Norton P. Peet
    Source: Drug discovery today
    Drug resistance is problematic in microbial disease, viral disease and cancer. Understanding at the outset that resistance will impact the effectiveness of any new drug that is developed for these d...
  • Molecular mechanisms of viral and host cell substrate recognition by hepatitis C virus NS3/4A protease

    July 22, 2011
    Author(s): Keith P. Romano, Jennifer M. Laine, Laura M. Deveau, Hong Cao, Francesca Massi, Celia A. Schiffer
    Source: Journal of virology
    Hepatitis C NS3/4A protease is a prime therapeutic target that is responsible for cleaving the viral polyprotein at junctions 3-4A, 4A4B, 4B5A, and 5A5B and two host cell adaptor proteins of the inn...
  • Dynamics of preferential substrate recognition in HIV-1 protease: redefining the substrate envelope

    July 19, 2011
    Author(s): Aysegul Ozen, Turkan Haliloglu, Celia A. Schiffer
    Source: Journal of molecular biology
    Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral the...
  • Three residues in HIV-1 matrix contribute to protease inhibitor susceptibility and replication capacity

    March 15, 2011
    Author(s): Chris M. Parry, Madhavi Kolli, Richard E. Myers, Patricia A. Cane, Celia A. Schiffer, Deenan Pillay
    Source: Antimicrobial agents and chemotherapy
    Other than cleavage site mutations, there is little data on specific positions within Gag that impact on HIV protease inhibitor susceptibility. We have recently shown that non-cleavage site mutation...
  • Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding

    December 07, 2010
    Author(s): Keith P. Romano, Akbar Ali, William E. Royer, Celia A. Schiffer
    Source: Proceedings of the National Academy of Sciences of the United States of America
    Hepatitis C virus infects an estimated 180 million people worldwide, prompting enormous efforts to develop inhibitors targeting the essential NS3/4A protease. Resistance against the most promising p...
  • Molecular Basis for Drug Resistance in HIV-1 Protease

    November 14, 2010
    Author(s): Akbar Ali, Rajintha M. Bandaranayake, Yufeng Cai, Nancy M. King, Madhavi Kolli, Seema Mittal, Jennifer E. Foulkes-Murzycki, Madhavi N. L. Nalam, Ellen A. Nalivaika, Aysegul Ozen, Moses Prabu-Jeyabalan...
    Source: Viruses
    HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-...
  • Structure-based design, synthesis, and structure-activity relationship studies of HIV-1 protease inhibitors incorporating phenyloxazolidinones

    November 11, 2010
    Author(s): Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi N. L. Nalam, Saima G. Anjum, Hong Cao, Celia A. Schiffer, Tariq M. Rana
    Source: Journal of medicinal chemistry
    A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different phenyloxazolidinone P2 ligands were designed and synthesized. Variation of phenyl substitutions at the P2 and ...
  • The effect of clade-specific sequence polymorphisms on HIV-1 protease activity and inhibitor resistance pathways

    October 28, 2010
    Author(s): Rajintha M. Bandaranayake, Madhavi Kolli, Nancy M. King, Ellen A. Nalivaika, Annie Heroux, Junko Kakizawa, Wataru Sugiura, Celia A. Schiffer
    Source: Journal of virology
    The majority of HIV-1 infections around the world result from non-B clade HIV-1 strains. The CRF01_AE (AE) strain is seen principally in Southeast Asia. AE protease differs by approximately 10% in a...
  • Therapeutic targeting of C-terminal binding protein in human cancer

    September 15, 2010
    Author(s): Michael W. Straza, Seema Paliwal, Ramesh C. Kovi, Barur R. Rajeshkumar, Peter Trenh, Daniel Parker, Giles F. Whalen, Stephen Lyle, Celia A. Schiffer, Steven R. Grossman
    Source: Cell cycle (Georgetown, Tex.)
    The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) t...
  • Rationale for more diverse inhibitors in competition with substrates in HIV-1 protease

    September 08, 2010
    Author(s): Nevra Ozer, Celia A. Schiffer, Turkan Haliloglu
    Source: Biophysical journal
    The structural fluctuations of HIV-1 protease in interaction with its substrates versus inhibitors were analyzed using the anisotropic network model. The directions of fluctuations in the most coope...
  • Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance

    May 20, 2010
    Author(s): Madhavi N. L. Nalam, Akbar Ali, Michael D. Altman, G. S. Kiran Kumar Reddy, Sripriya Chellappan, Visvaldas Kairys, Aysegul Ozen, Hong Cao, Michael K. Gilson, Bruce Tidor, Tariq M. Rana, Celia A. Schif...
    Source: Journal of virology
    Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to...
  • Decomposing the energetic impact of drug resistant mutations in HIV-1 protease on binding DRV

    April 15, 2010
    Author(s): Yufeng Cai, Celia A. Schiffer
    Source: Journal of chemical theory and computation
    Darunavir (DRV) is a high affinity (4.5x10(-12) M, DeltaG = -15.2 kcal/mol) HIV-1 protease inhibitor. Two drug-resistant protease variants FLAP+ (L10I, G48V, I54V, V82A) and ACT (V82T, I84V) decreas...
  • Crystal structure of the APOBEC3G catalytic domain reveals potential oligomerization interfaces.

    January 13, 2010
    Author(s): Shivender Shandilya, Madhavi N. L. Nalam, Ellen A. Nalivaika, Phillip J. Gross, Johnathan C. Valesano, Keisuke Shindo, Ming Li, Mary Munson, William E. Royer, Elena Harjes, Takahide Kono, Hiroshi Mats...
    Source: Structure (London, England)
    APOBEC3G is a DNA cytidine deaminase that has antiviral activity against HIV-1 and other pathogenic viruses. In this study the crystal structure of the catalytically active C-terminal domain was det...
  • Human immunodeficiency virus type 1 protease-correlated cleavage site mutations enhance inhibitor resistance

    August 27, 2009
    Author(s): Madhavi Kolli, Eric Stawiski, Colombe Chappey, Celia A. Schiffer
    Source: Journal of virology
    Drug resistance is an important cause of antiretroviral therapy failure in human immunodeficiency virus (HIV)-infected patients. Mutations in the protease render the virus resistant to protease inhi...
  • Toward the design of mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis

    August 26, 2009
    Author(s): Visvaldas Kairys, Michael K. Gilson, Viney Lather, Celia A. Schiffer, Miguel X. Fernandes
    Source: Chemical biology and drug design
    Previous studies have shown the usefulness of the substrate envelope concept in the analysis and prediction of drug resistance profiles for human immunodeficiency virus protease mutants. This study ...
  • New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors

    April 18, 2009
    Author(s): Madhavi N. L. Nalam, Celia A. Schiffer
    Source: Current opinion in HIV and AIDS
    PURPOSE OF REVIEW: Drug resistance results when the balance between the binding of inhibitors and the turnover of substrates is perturbed in favor of the substrates. Resistance is quite widespread t...
  • Additivity in the analysis and design of HIV protease inhibitors

    February 06, 2009
    Author(s): Robert N. Jorissen, G. S. Kiran Kumar Reddy, Akbar Ali, Michael D. Altman, Sripriya Chellappan, Saima G. Anjum, Bruce Tidor, Celia A. Schiffer, Tariq M. Rana, Michael K. Gilson
    Source: Journal of medicinal chemistry
    We explore the applicability of an additive treatment of substituent effects to the analysis and design of HIV protease inhibitors. Affinity data for a set of inhibitors with a common chemical frame...
  • Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5

    October 07, 2008
    Author(s): Weijun Chen, Suvana S. Lam, Hema Srinath, Zhaozhao Jiang, John J. Correia, Celia A. Schiffer, Katherine A. Fitzgerald, Kai Lin, William E. Royer
    Source: Nature structural and molecular biology
    Interferon regulatory factors (IRFs) are essential in the innate immune response and other physiological processes. Activation of these proteins in the cytoplasm is triggered by phosphorylation of s...
  • Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir

    September 30, 2008
    Author(s): Eric Lefebvre, Celia A. Schiffer
    Source: AIDS reviews
    The current effectiveness of HAART in the management of HIV infection is compromised by the emergence of extensively cross-resistant strains of HIV-1, requiring a significant need for new therapeuti...
  • Structural analysis of human immunodeficiency virus type 1 CRF01_AE protease in complex with the substrate p1-p6.

    July 01, 2008
    Author(s): Rajintha M. Bandaranayake, Moses Prabu-Jeyabalan, Junko Kakizawa, Wataru Sugiura, Celia A. Schiffer
    Source: Journal of virology
    The effect of amino acid variability between human immunodeficiency virus type 1 (HIV-1) clades on structure and the emergence of resistance mutations in HIV-1 protease has become an area of signifi...
  • Contribution of Ser386 and Ser396 to activation of interferon regulatory factor 3

    April 29, 2008
    Author(s): Weijun Chen, Hema Srinath, Suvana S. Lam, Celia A. Schiffer, William E. Royer, Kai Lin
    Source: Journal of molecular biology
    IRF-3, a member of the interferon regulatory factor (IRF) family of transcription factors, functions in innate immune defense against viral infection. Upon infection, host cell IRF-3 is activated by...
  • HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants

    April 17, 2008
    Author(s): Michael D. Altman, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi N. L. Nalam, Saima G. Anjum, Hong Cao, Sripriya Chellappan, Visvaldas Kairys, Miguel X. Fernandes, Michael K. Gilson, Celia A. Schiffer, ...
    Source: Journal of the American Chemical Society
    The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a g...
  • Combating Drug Resistance – Identifying Resilient Molecular Targets and Robust Drugs

    January 01, 2008
    Author(s): Celia A. Schiffer
    Source: Computational and Structural Approaches to Drug Discovery: Ligand-Protein Interactions
  • Mass spectrometry analysis of HIV-1 Vif reveals an increase in ordered structure upon oligomerization in regions necessary for viral infectivity

    November 01, 2007
    Author(s): Jared R. Auclair, Karin M. Green, Shivender Shandilya, James E. Evans, Mohan Somasundaran, Celia A. Schiffer
    Source: Proteins
    HIV-1 Vif, an accessory protein in the viral genome, performs an important role in viral pathogenesis by facilitating the degradation of APOBEC3G, an endogenous cellular inhibitor of HIV-1 replicati...
  • Computational design and experimental study of tighter binding peptides to an inactivated mutant of HIV-1 protease

    August 31, 2007
    Author(s): Michael D. Altman, Ellen A. Nalivaika, Moses Prabu-Jeyabalan, Celia A. Schiffer, Bruce Tidor
    Source: Proteins
    Drug resistance in HIV-1 protease, a barrier to effective treatment, is generally caused by mutations in the enzyme that disrupt inhibitor binding but still allow for substrate processing. Structura...
  • Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2' ligands in pseudosymmetric dipeptide isosteres

    August 19, 2007
    Author(s): G. S. Kiran Kumar Reddy, Akbar Ali, Madhavi N. L. Nalam, Saima G. Anjum, Hong Cao, Robin S. Nathans, Celia A. Schiffer, Tariq M. Rana
    Source: Journal of medicinal chemistry
    A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have been synthesized and evaluated. The inhibitors were designed by incorporating N-phenyloxazolidinone-...
  • Crystal structure of lysine sulfonamide inhibitor reveals the displacement of the conserved flap water molecule in human immunodeficiency virus type 1 protease

    June 29, 2007
    Author(s): Madhavi N. L. Nalam, Anik Peeters, Tim H. M. Jonckers, Inge Dierynck, Celia A. Schiffer
    Source: Journal of virology
    Human immunodeficiency virus type 1 (HIV-1) protease has been continuously evolving and developing resistance to all of the protease inhibitors. This requires the development of new inhibitors that ...
  • Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis

    June 02, 2007
    Author(s): Sripriya Chellappan, G. S. Kiran Kumar Reddy, Akbar Ali, Madhavi N. L. Nalam, Saima G. Anjum, Hong Cao, Visvaldas Kairys, Miguel X. Fernandes, Michael D. Altman, Bruce Tidor, Tariq M. Rana, Celia A. S...
    Source: Chemical biology and drug design
    There is a clinical need for HIV protease inhibitors that can evade resistance mutations. One possible approach to designing such inhibitors relies upon the crystallographic observation that the sub...
  • Evaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease

    May 03, 2007
    Author(s): Sripriya Chellappan, Visvaldas Kairys, Miguel X. Fernandes, Celia A. Schiffer, Michael K. Gilson
    Source: Proteins
    Crystallographic data show that various substrates of HIV protease occupy a remarkably uniform region within the binding site; this region has been termed the substrate envelope. It has been suggest...
  • Hydrophobic sliding: a possible mechanism for drug resistance in human immunodeficiency virus type 1 protease

    February 13, 2007
    Author(s): Jennifer E. Foulkes-Murzycki, Walter Robert Peter Scott, Celia A. Schiffer
    Source: Structure (London, England : 1993)
    Hydrophobic residues outside the active site of HIV-1 protease frequently mutate in patients undergoing protease inhibitor therapy; however, the mechanism by which these mutations confer drug resist...
  • Competition between Ski and CREB-binding protein for binding to Smad proteins in transforming growth factor-beta signaling

    February 07, 2007
    Author(s): Weijun Chen, Suvana S. Lam, Hema Srinath, Celia A. Schiffer, William E. Royer, Kai Lin
    Source: The Journal of biological chemistry
    The family of Smad proteins mediates transforming growth factor-beta (TGF-beta) signaling in cell growth and differentiation. Smads repress or activate TGF-beta signaling by interacting with corepre...
  • N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure

    January 11, 2007
    Author(s): Yumi Mitsuya, Mark A. Winters, W. Jeffrey Fessel, Soo-Yon Rhee, Leo Hurley, Michael Horberg, Celia A. Schiffer, Andrew R. Zolopa, Robert W. Shafer
    Source: AIDS research and human retroviruses
    Nelfinavir was once one of the most commonly used protease inhibitors (PIs). To investigate the genetic mechanisms of multidrug resistance in protease isolates with the primary nelfinavir resistance...
  • Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5-carboxamides as novel P2 ligands

    December 08, 2006
    Author(s): Akbar Ali, G. S. Kiran Kumar Reddy, Hong Cao, Saima G. Anjum, Madhavi N. L. Nalam, Celia A. Schiffer, Tariq M. Rana
    Source: Journal of medicinal chemistry (3-(3-acetylphenyl)-N-(1-benzyl-2-hydroxy-3-(isobutyl((4-methoxyphenyl)sul fonyl)amino)propyl)-2-oxooxazolidine-5-carboxamide)
    Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaff...
  • RecA dimers serve as a functional unit for assembly of active nucleoprotein filaments

    November 08, 2006
    Author(s): Anthony L. Forget, Michelle M. Kudron, Dharia A. McGrew, Melissa A. Calmann, Celia A. Schiffer, Kendall L. Knight
    Source: Biochemistry
    All RecA-like recombinase enzymes catalyze DNA strand exchange as elongated filaments on DNA. Despite numerous biochemical and structural studies of RecA and the related Rad51 and RadA proteins, the...
  • Role of invariant Thr80 in human immunodeficiency virus type 1 protease structure, function, and viral infectivity

    July 01, 2006
    Author(s): Jennifer E. Foulkes-Murzycki, Moses Prabu-Jeyabalan, Deyna Cooper, Gavin J. Henderson, Janera Harris, Ronald I. Swanstrom, Celia A. Schiffer
    Source: Journal of virology
    Sequence variability associated with human immunodeficiency virus type 1 (HIV-1) is useful for inferring structural and/or functional constraints at specific residues within the viral protease. Posi...
  • Substrate specificity in HIV-1 protease by a biased sequence search method

    June 03, 2006
    Author(s): Nevra Ozer, Turkan Haliloglu, Celia A. Schiffer
    Source: Proteins
    Drug resistance in HIV-1 protease can also occasionally confer a change in the substrate specificity. Through the use of computational techniques, a relationship can be determined between the substr...
  • Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate

    April 10, 2006
    Author(s): Madhavi Kolli, Stephane Lastere, Celia A. Schiffer
    Source: Virology
    The selective pressure of the competitive protease inhibitors causes both HIV-1 protease and occasionally its substrates to evolve drug resistance. We hypothesize that this occurs particularly in su...
  • Substrate envelope and drug resistance: crystal structure of RO1 in complex with wild-type human immunodeficiency virus type 1 protease

    March 30, 2006
    Author(s): Moses Prabu-Jeyabalan, Nancy M. King, Ellen A. Nalivaika, Gabrielle Heilek-Snyder, Nick Cammack, Celia A. Schiffer
    Source: Antimicrobial agents and chemotherapy
    In our previous crystallographic studies of human immunodeficiency virus type 1 (HIV-1) protease-substrate complexes, we described a conserved "envelope" that appears to be important for substrate r...
  • Mechanism of substrate recognition by drug-resistant human immunodeficiency virus type 1 protease variants revealed by a novel structural intermediate

    March 16, 2006
    Author(s): Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Keith Romano, Celia A. Schiffer
    Source: Journal of virology
    Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves the Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore is an important target for antiviral therapy. Li...
  • PTEN enters the nucleus by diffusion

    August 10, 2005
    Author(s): Fenghua Liu, Stefan R. Wagner, Robert B. Campbell, Jeffrey A. Nickerson, Celia A. Schiffer, Alonzo H. Ross
    Source: Journal of cellular biochemistry
    Despite much evidence for phosphatidylinositol phosphate (PIP)-triggered signaling pathways in the nucleus, there is little understanding of how the levels and activities of these proteins are regul...
  • Design of HIV-1 protease inhibitors active on multidrug-resistant virus

    March 18, 2005
    Author(s): Dominique L. N. G. S Surleraux, Herman A. De Kock, Wim G. Verschueren, Geert M. E. Pille, Louis J. R. Maes, Anik Peeters, Sandrine Vendeville, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre ...
    Source: Journal of medicinal chemistry
    On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroa...
  • Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor

    March 18, 2005
    Author(s): Dominique L. N. G. S Surleraux, Abdellah Tahri, Wim G. Verschueren, Geert M. E. Pille, Herman A. De Kock, Tim H. M. Jonckers, Anik Peeters, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre de ...
    Source: Journal of medicinal chemistry
    The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the im...
  • Association of a novel human immunodeficiency virus type 1 protease substrate cleft mutation, L23I, with protease inhibitor therapy and in vitro drug resistance

    November 25, 2004
    Author(s): Elizabeth Johnston, Mark A. Winters, Soo-Yon Rhee, Thomas C. Merigan, Celia A. Schiffer, Robert W. Shafer
    Source: Antimicrobial agents and chemotherapy
    We observed a previously uncharacterized mutation in the protease substrate cleft, L23I, in 31 of 4,303 persons undergoing human immunodeficiency virus type 1 genotypic resistance testing. In combin...
  • Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-p1 cleavage site with a V82A drug-resistant mutation in viral protease

    October 28, 2004
    Author(s): Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
    Source: Journal of virology
    Maturation of human immunodeficiency virus (HIV) depends on the processing of Gag and Pol polyproteins by the viral protease, making this enzyme a prime target for anti-HIV therapy. Among the protea...
  • Combating susceptibility to drug resistance: lessons from HIV-1 protease

    October 19, 2004
    Author(s): Nancy M. King, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Celia A. Schiffer
    Source: Chemistry and biology
    Drug resistance is a major obstacle in modern medicine. However, resistance is rarely considered in drug development and may inadvertently be facilitated, as many designed inhibitors contact residue...
  • Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor

    October 14, 2004
    Author(s): Nancy M. King, Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Piet B. T. P. Wigerinck, Marie-Pierre de Bethune, Celia A. Schiffer
    Source: Journal of virology
    TMC114, a newly designed human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is extremely potent against both wild-type (wt) and multidrug-resistant (MDR) viruses in vitro as well as in ...
  • Promise of advances in simulation methods for protein crystallography: implicit solvent models, time-averaging refinement, and quantum mechanical modeling

    December 31, 2003
    Author(s): Celia A. Schiffer, Jan Hermans
    Source: Methods in enzymology
  • Covariation of amino acid positions in HIV-1 protease

    October 14, 2003
    Author(s): Noah G. Hoffman, Celia A. Schiffer, Ronald I. Swanstrom
    Source: Virology
    We have examined patterns of sequence variability for evidence of linked sequence changes in HIV-1 subtype B protease using translated sequences from protease inhibitor (PI) treated and untreated su...
  • Structure-based prediction of potential binding and nonbinding peptides to HIV-1 protease

    July 30, 2003
    Author(s): Nese Kurt, Turkan Haliloglu, Celia A. Schiffer
    Source: Biophysical journal
    HIV-1 protease is a major drug target against AIDS as it permits viral maturation by processing the gag and pol polyproteins of the virus. The cleavage sites in these polyproteins do not have obviou...
  • Cooperative fluctuations of unliganded and substrate-bound HIV-1 protease: a structure-based analysis on a variety of conformations from crystallography and molecular dynamics simulations

    April 16, 2003
    Author(s): Nese Kurt, Walter Robert Peter Scott, Celia A. Schiffer, Turkan Haliloglu
    Source: Proteins
    The dynamics of HIV-1 protease, both in unliganded and substrate-bound forms have been analyzed by using an analytical method, Gaussian network model (GNM). The method is applied to different confor...
  • Mutation patterns and structural correlates in human immunodeficiency virus type 1 protease following different protease inhibitor treatments

    March 29, 2003
    Author(s): Thomas D. Wu, Celia A. Schiffer, Matthew J. Gonzales, Jonathan Taylor, Rami Kantor, Sunwen Chou, Dennis Israelski, Andrew R. Zolopa, W. Jeffrey Fessel, Robert W. Shafer
    Source: Journal of virology
    Although many human immunodeficiency virus type 1 (HIV-1)-infected persons are treated with multiple protease inhibitors in combination or in succession, mutation patterns of protease isolates from ...
  • Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy

    December 28, 2002
    Author(s): Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Nancy M. King, Celia A. Schiffer
    Source: Journal of virology
    Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutati...
  • Nitric oxide-mediated inhibition of Hdm2-p53 binding

    November 13, 2002
    Author(s): Christopher M. Schonhoff, Marie-Claire Daou, Stephen N. Jones, Celia A. Schiffer, Alonzo H. Ross
    Source: Biochemistry
    It has become increasingly evident that nitric oxide exerts its effects, in part, by S-nitrosylation of cysteine residues. We tested in vitro whether nitric oxide may indirectly control p53 by S-nit...
  • Point mutants of EHEC intimin that diminish Tir recognition and actin pedestal formation highlight a putative Tir binding pocket

    October 02, 2002
    Author(s): Hui Liu, Padhma Radhakrishnan, Loranne Magoun, Moses Prabu-Jeyabalan, Kenneth Geno Campellone, Pamela Joyce Savage, Feng He, Celia A. Schiffer, John M. Leong
    Source: Molecular microbiology
    Attachment to host cells by enterohaemorrhagic Escherichia coli (EHEC) is associated with the formation of a highly organized cytoskeletal structure containing filamentous actin, termed an attaching...
  • Replacement of the P1 amino acid of human immunodeficiency virus type 1 Gag processing sites can inhibit or enhance the rate of cleavage by the viral protease

    September 20, 2002
    Author(s): Steve C. Pettit, Gavin J. Henderson, Celia A. Schiffer, Ronald I. Swanstrom
    Source: Journal of virology
    Processing of the human immunodeficiency virus type 1 (HIV-1) Gag precursor is highly regulated, with differential rates of cleavage at the five major processing sites to give characteristic process...
  • Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes

    May 15, 2002
    Author(s): Moses Prabu-Jeyabalan, Ellen A. Nalivaika, Celia A. Schiffer
    Source: Structure (London, England : 1993)
    The homodimeric HIV-1 protease is the target of some of the most effective antiviral AIDS therapy, as it facilitates viral maturation by cleaving ten asymmetric and nonhomologous sequences in the Ga...