Interface of Evolution and Structure Based Drug Design

Our Lab

Constraining evolution and avoiding drug resistance

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Drug resistance occurs when, through evolution, a disease no longer responds to medications. Resistance impacts the lives of millions, limiting the effectiveness of many of our most potent drugs. This often happens under the selective pressure of therapy in bacterial, viral and fungal infections and cancer due to their rapid evolution.

We combine a variety of experimental and computational techniques to understand the molecular basis of drug resistance. Our new paradigm of drug design minimizes chances of resistance. Realizing that disrupting the drug target’s activity is necessary but not sufficient for developing a robust drug that avoids resistance.

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Research Focus

Strategies and Systems

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We use multidisciplinary approaches, combining crystallography, enzymology, molecular dynamics and organic chemistry, to elucidate the molecular mechanisms of drug resistance. Resistance occurs when a heterogeneous populations of a drug target is challenged by the selective pressure of a drug. In cancer and viruses this heterogeneity is partially caused APOBEC3’s. We discovered resistance mutations occur either where drugs physically contact regions of the drug target that are not essential for substrate recognition or alter the ensemble dynamics of the drug target favoring substrate. We leverage these insights into a new strategies in structure-based drug design to minimize the likelihood for resistance by designing inhibitors to stay within the substrate envelope. This strategy not only describes most of the primary drug resistance for HIV, Hepatitis C viral protease inhibitors and influenza neuraminidase, but is generally applicable in the development of novel drugs that are less susceptible to resistance.

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Publications

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Total: 1 results
  • Constrained Mutational Sampling of Amino Acids in HIV-1 Protease Evolution.

    Author(s): Boucher JI, Whitfield TW, Dauphin A, Nachum G, Hollins C, Zeldovich KB, Swanstrom R, Schiffer CA, Luban J, Bolon DNA
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    Constrained Mutational Sampling of Amino Acids in HIV-1 Protease Evolution.

    Mol Biol Evol. 2019 04 01;36(4):798-810

    Authors: Boucher JI, Whitfield TW, Dauphin A, Nachum G, Hollins C, Zeldovich KB, Swanstrom R, Schiffer CA, Luban J, Bolon DNA

    Abstract
    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 protein sequence evolution is interdependent, making it challenging to infer the individual contribution of each factor from phylogenetic analyses alone. We investigated the protein sequence evolution of HIV-1 by determining an experimental fitness landscape of all individual amino acid changes in protease. We compared our experimental results to the frequency of protease variants in a publicly available data set of 32,163 sequenced isolates from drug-naïve individuals. The most common amino acids in sequenced isolates supported robust experimental fitness, indicating that the experimental fitness landscape captured key features of selection acting on protease during viral infections of hosts. Amino acid changes requiring multiple mutations from the likely ancestor were slightly less likely to support robust experimental fitness than single mutations, consistent with the genetic code favoring chemically conservative amino acid changes. Amino acids that were common in sequenced isolates were predominantly accessible by single mutations from the likely protease ancestor. Multiple mutations commonly observed in isolates were accessible by mutational walks with highly fit single mutation intermediates. Our results indicate that the prevalence of multiple-base mutations in HIV-1 protease is strongly influenced by mutational sampling.

    PMID: 30721995 [PubMed - indexed for MEDLINE]

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Contact Us

Office:
Lazare Research Building 828
Campus Map (pdf)

Phone:
508-856-8008 (office)

Email:
Celia.Schiffer@umassmed.edu

Mailing Address:
University of Massachusetts Medical School
Attn: Dr. Celia Schiffer/BMP department
364 Plantation St LRB828
Worcester, MA 01605

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We are always interested in applications from qualified candidates at postdoctoral and research associate levels.

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Undergraduates interested in pursuing a PhD at UMass Medical School should apply directly to the Graduate School of Biomedical Sciences Program.