Publication Date

2016-04-06

Document Type

Doctoral Dissertation

Academic Program

MD/PhD

Department

Department of Biochemistry and Molecular Pharmacology

First Thesis Advisor

Celia A. Schiffer, Ph.D.

Keywords

drug resistance, antibody neutralization, antivirals, influenza

Subjects

Dissertations, UMMS; Antibodies, Neutralizing; Antiviral Agents; Drug Resistance, Viral; Hemagglutinins; Hepacivirus; Influenza, Human; Neuraminidase; Molecular Dynamics Simulation; Protease Inhibitors

Abstract

Antiviral drug resistance is a major problem in the treatment of viral infections, including influenza and hepatitis C virus (HCV). Influenza neuraminidase (NA) is a viral sialidase on the surface of the influenza virion and a primary antiviral target in influenza. Two subtypes of NA predominate in humans, N1 and N2, but different patterns of drug resistance have emerged in each subtype. To provide a framework for understanding the structural basis of subtype specific drug resistance mutations in NA, we used molecular dynamics simulations to define dynamic substrate envelopes for NA to determine how different patterns of drug resistance have emerged in N1 and N2 NA. Furthermore, we used the substrate envelope to analyze HCV NS3/4A protease inhibitors in clinical development. In addition, influenza hemagglutinin (HA) is a primary target of neutralizing antibodies against influenza. Novel broadly neutralizing antibodies (BnAbs) against the stem region of HA have been described and inhibit several influenza viral subtypes, but antibody neutralization escape mutations have emerged. We identified potential escape mutations in broadly neutralizing antibody F10 that may impact protein dynamics in HA that are critical for function. We also solved crystal structures of antibody fragments that are important for understanding the structural basis of antibody binding for influenza BnAbs. These studies can inform the design of improved therapeutic strategies against viruses by incorporating an understanding of structural elements that are critical for function, such as substrate processing and protein dynamics, into the development of novel therapeutics that are robust against resistance.

Comments

Title on signature page: Understanding Antiviral Drug Resistance and Molecular Recognition in Influenza Broadly Neutralizing Antibodies.

DOI

10.13028/M2C01X

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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