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Understanding Drug Resistance and Antibody Neutralization Escape in Antivirals: a Dissertation

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Understanding Drug Resistance and Antibody Neutralization Escape in Antivirals: a Dissertation University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2016-04-06 Understanding Drug Resistance and Antibody Neutralization Escape in Antivirals: A Dissertation Kristina L. Prachanronarong University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Biochemistry Commons, Biophysics Commons, Cellular and Molecular Physiology Commons, Immunoprophylaxis and Therapy Commons, Pharmacology Commons, Structural Biology Commons, Virology Commons, and the Virus Diseases Commons Repository Citation Prachanronarong KL. (2016). Understanding Drug Resistance and Antibody Neutralization Escape in Antivirals: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/M2C01X. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/840 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. UNDERSTANDING DRUG RESISTANCE AND ANTIBODY NEUTRALIZATION ESCAPE IN ANTIVIRALS A Dissertation Presented By KRISTINA PRACHANRONARONG Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY APRIL 6, 2016 MD/PHD PROGRAM ii UNDERSTANDING ANTIVIRAL DRUG RESISTANCE AND MOLECULAR RECOGNITION IN INFLUENZA BROADLY NEUTRALIZING ANTIBODIES A Dissertation Presented By KRISTINA PRACHANRONARONG This work was undertaken in the Graduate School of Biomedical Sciences MD/PHD PROGRAM The signature of the Thesis Advisor signifies validation of Dissertation content CELIA A. SCHIFFER, PH.D., Thesis Advisor The signatures of the Dissertation Defense Committee signify Completion and approval as to style and content of the Dissertation DAN BOLON, PH.D., Member of Committee FRANCESCA MASSI, PH.D., Member of Committee JENNIFER WANG, M.D., Member of Committee SCOTT GARMAN, PH.D., Member of Committee The signature of the Chair of the Committee signifies that the written dissertation meets the requirements of the Dissertation Committee LAWRENCE STERN, PH.D., Chair of Committee The signature of the Dean of the Graduate School of Biomedical Sciences signifies that the student has met all graduation requirements of the School. ANTHONY CARRUTERS, PH.D. Dean of the Graduate School of Biomedical Sciences APRIL 6, 2016 iii TABLE OF CONTENTS Page ABSTRACT ..........................................................................................................vii LIST OF TABLES ................................................................................................. ix LIST OF FIGURES................................................................................................ x LIST OF THIRD PARTY COPYRIGHTED MATERIAL!........................................xiv PREFACE...........................................................................................................xvii 1 Introduction ...................................................................................................... 1 1.1 Therapeutic Strategies Against Viruses ............................................... 1 1.2 Structure Based Drug Design in Antivirals ........................................... 7 1.3 Drug Resistance and Antibody Neutralization Escape in Antivirals .......................................................................................... 8 1.3.1 Resistance to Competitive Small Molecule Antivirals and the Substrate Envelope................................................ 10 1.3.2 Resistance to Antibodies as Therapeutics: Antibody Neutralization Escape ......................................................... 14 1.4 Protein Dynamics in Molecular Recognition ....................................... 17 1.4.1 Role of Protein Dynamics in Antiviral Resistance ............... 18 1.4.2 Role of Protein Dynamics in Antibody Neutralization Escape ................................................................................ 19 1.5 Scope of Thesis.................................................................................. 19 2 THE SUBSTRATE ENVELOPE HYPOTHESIS DESCRIBES DIFFERENTIAL PATTERNS OF DRUG RESISTANCE IN N1 AND N2 NEURAMINIDASE!............................................................................................... 22 2.1 Abstract .............................................................................................. 22 2.2 Introduction......................................................................................... 23 2.3 Results................................................................................................ 29 2.3.1 Description of Molecular Dynamics Simulations ................. 29 2.3.2 Static and Dynamic Substrate and Inhibitor Envelopes ...... 35 2.3.3 Differences in Van der Waals Contacts Correlate with Differential Patterns of Drug Resistance in N1 and N2....... 45 2.3.4 Hydrogen Bond Interactions ................................................. 57 2.4 Discussion .......................................................................................... 58 2.5 Methods.............................................................................................. 61 2.5.1 Influenza Neuraminidase Substrate and Inhibitor Complex Structures!............................................................. 61 2.5.2 Structure Preparation.......................................................... 62 2.5.3 Molecular Dynamics Simulation Protocol............................ 63 2.5.4 Root Mean Squared Deviation (RMSD).............................. 63 2.5.5 Root Mean Squared Fluctuation (RMSF) and SimulationdDerived Temperature Factors ........................... 64 2.5.6 Dynamic Substrate Envelope.............................................. 64 2.5.7 Van der Waals Contact Potential ........................................ 65 iv 2.5.8 Hydrogen Bond Calculations .............................................. 65 2.5.9 Plots and Figures ................................................................ 66 3 COMPARATIVE ANALYSIS OF HEPATITIS C NS3/4A INHIBITOR STRUCTURES.................................................................................................... 67 3.1 Abstract .............................................................................................. 67 3.2 Introduction......................................................................................... 68 3.2.1 HCV NS3/4A Protease and Current Inhibitors .................... 70 3.2.2 Drug Resistance to HCV NS3/4A Protease Inhibitors ........ 79 3.3 Results................................................................................................ 83 3.3.1 Substrate Envelope and VIN and VOUT ................................ 83 3.3.2 InhibitordProtease Contacts at the Active Site .................... 91 3.3.3 Hydrogen Bond Interactions ............................................. 102 3.4 Discussion ........................................................................................ 108 3.5 Methods............................................................................................ 109 3.5.1 Substrate Envelope and VIN and VOUT Calculations.......... 109 3.5.2 Van der Waals Contact Potential Energy.......................... 111 3.5.3 Hydrogen Bond Interactions ............................................. 112 3.5.4 Plots and Figures .............................................................. 112 4 IDENTIFICATION OF INFLUENZA A VIRUS CANDIDATE RESISTANCE MUTATIONS TO BROADLY NEUTRALIZING ANTIBODY ...... 113 4.1 Abstract ............................................................................................ 113 4.2 Introduction....................................................................................... 114 4.3 Results.............................................................................................. 118 4.3.1 Serial passage of influenza in the presence of F10 monoclonal antibody ......................................................... 118 4.3.2 Sequence analysis reveals candidate F10 escape mutations!........................................................................... 122 4.3.3 Structural mapping of candidate F10 hemagglutinin escape mutants................................................................. 122 4.3.4 Potential impact of specific mutations on hemagglutinin function ...................................................... 123 4.3.5 Neuraminidase mutant...................................................... 137 4.3.6 PA, PB1, and synonymous mutants ................................. 137 4.4 Discussion ........................................................................................ 138 4.5 Conclusion........................................................................................ 143 4.6 Methods............................................................................................ 144 4.6.1 Cells, virus stocks, and chemicals. ................................... 144 4.6.2 Viral titer determination by plaque assay .......................... 144 4.6.3 Determination of the ED50 for F10 antibody ...................... 145 4.6.4 Viral culture ....................................................................... 145 4.6.5 Highdthroughput sequencing............................................
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