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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
  • Mutations in Influenza A Virus Neuraminidase and Hemagglutinin Confer Resistance against a Broadly Neutralizing Hemagglutinin Stem Antibody.

    Author(s): Prachanronarong KL, Canale AS, Liu P, Somasundaran M, Hou S, Poh YP, Han T, Zhu Q, Renzette N, Zeldovich KB, Kowalik TF, Kurt-Yilmaz N, Jensen JD, Bolon DNA, Marasco WA, Finberg RW, Schiffer CA, Wang JP
    Icon for PubMed Central Related Articles

    Mutations in Influenza A Virus Neuraminidase and Hemagglutinin Confer Resistance against a Broadly Neutralizing Hemagglutinin Stem Antibody.

    J Virol. 2019 01 15;93(2):

    Authors: Prachanronarong KL, Canale AS, Liu P, Somasundaran M, Hou S, Poh YP, Han T, Zhu Q, Renzette N, Zeldovich KB, Kowalik TF, Kurt-Yilmaz N, Jensen JD, Bolon DNA, Marasco WA, Finberg RW, Schiffer CA, Wang JP

    Abstract
    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 the influenza virus hemagglutinin (HA) are a promising therapeutic strategy, but neutralization escape mutants can develop. We used an integrated approach combining viral passaging, deep sequencing, and protein structural analyses to define escape mutations and mechanisms of neutralization escape in vitro for the F10 sBnAb. IAV was propagated with escalating concentrations of F10 over serial passages in cultured cells to select for escape mutations. Viral sequence analysis revealed three mutations in HA and one in neuraminidase (NA). Introduction of these specific mutations into IAV through reverse genetics confirmed their roles in resistance to F10. Structural analyses revealed that the selected HA mutations (S123G, N460S, and N203V) are away from the F10 epitope but may indirectly impact influenza virus receptor binding, endosomal fusion, or budding. The NA mutation E329K, which was previously identified to be associated with antibody escape, affects the active site of NA, highlighting the importance of the balance between HA and NA function for viral survival. Thus, whole-genome population sequencing enables the identification of viral resistance mutations responding to antibody-induced selective pressure.IMPORTANCE Influenza A virus is a public health threat for which currently available vaccines are not always effective. Broadly neutralizing antibodies that bind to the highly conserved stem region of the influenza virus hemagglutinin (HA) can neutralize many influenza virus strains. To understand how influenza virus can become resistant or escape such antibodies, we propagated influenza A virus in vitro with escalating concentrations of antibody and analyzed viral populations by whole-genome sequencing. We identified HA mutations near and distal to the antibody binding epitope that conferred resistance to antibody neutralization. Additionally, we identified a neuraminidase (NA) mutation that allowed the virus to grow in the presence of high concentrations of the antibody. Virus carrying dual mutations in HA and NA also grew under high antibody concentrations. We show that NA mutations mediate the escape of neutralization by antibodies against HA, highlighting the importance of a balance between HA and NA for optimal virus function.

    PMID: 30381484 [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

Join Us

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.

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