Antiviral characterization and Anti-reactivation properties of pyrrolopyridine based ALLINIs STP0404 and EKC110 Restricted; Files Only

Abstract

HIV-1 establishes lifelong infection in transcriptionally inactive but replication competent/resting CD4+ T cells by integrating proviral DNAs into the host chromosomes. HIV-1 integrase (IN) dimers bind to host LEDGF/p75 protein during viral integration. Transcription activator LEDGF/p75 tethers the IN-proviral DNA complex (pre-integration complex) for integration specifically to transcriptionally active regions of the chromosomes, facilitating HIV-1 transcription from the virally encoded promoter. Allosteric IN inhibitors (ALLINIs) are a new class of IN inhibitors targeting non-catalytic sites of HIV-1 IN. STP0404 and new 2nd-generation EKC110 ALLINI compound have been proposed to have improved genetic barrier and possible utility as an HIV-1 cure agent. Here, we report the comparison ALLINIs STP0404 and EKC110 antiviral efficacy, cellular cytotoxicity and optimization of methodology for identification of drug resistant mutations against ALLINI compounds. Furthermore, we have demonstrated that STP0404 displays HIV anti-reactivation properties in-vitro and proof of concept for future characterization and comparison of ALLINIs potential utility as a 'lock and block' curative agent. 

Table of Contents

Abstract.............................................................................................................................2

List of Tables....................................................................................................................5

List of Figures...................................................................................................................6

Chapter 1: Introduction..................................................................................................7

1.1: Overview; HIV and AIDS................................................................................7

1.2 Anti-Retroviral Therapy...................................................................................8

1.3 The HIV Reservoir.........................................................................................10

            1.4 Integrase .......................................................................................................11

            1.5: LEDGF/p75...................................................................................................12

            1.6: ALLINIs STP0404 and EKC110 structural optimization ..............................13

            1.7: Hypothesis and Objectives of this research..................................................15

Chapter 2: ALLINIs STP0404 and EKC110 antiviral and anti-reactivation properties

            2.1: Introduction...................................................................................................16

            2.2: Antiviral properties........................................................................................17

            2.3: Anti-reactivation properties...........................................................................18

            2.4: Drug resistant selection methodology and optimization................................19

            2.5: Materials and Methods..................................................................................21

            2.6 Discussion......................................................................................................25

            2.7 Tables............................................................................................................29

            2.8 Figures...........................................................................................................30

Acknowledgements......................................................................................................36

References....................................................................................................................37

About this Master's Thesis

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Molecular & Systems Pharmacology
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Biology, Virology Biology, Molecular
Mot-clé	antiviral pharmacology
Committee Chair / Thesis Advisor	Baek Kim, Emory University
Committee Members	Christina Gavegnano, Emory University Christopher Doering, Emory University Cassandra Quave, Emory University

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