Glyoxal-based Caging of Nucleoside Reverse Transcriptase Inhibitors for the Treatment of Viral Infections Open Access

Abstract

Viral infections pose a significant public health challenge, leading to both acute pandemic events such as the current COVID-19 outbreak and long-lasting endemic challenges such as HIV prevalence in Africa. Nucleoside reverse transcriptase inhibitors (NRTIs) are a leading class of antiretroviral compounds often prescribed as a first-line treatment for viral infections. However, they have inherent limitations such as low solubility and circulation lifetime that often necessitate multi-intraday dosing. These factors compromise patient adherence, in turn contributing to poor patient outcomes and increased antiretroviral drug resistance. Current solutions to combat these challenges have primarily focused on the development of novel pharmaceuticals; however, these efforts require extensive time and resources, and discoveries are specific to each chemical entity. A promising alternative is the elaboration of currently approved therapeutics into prodrug moieties, as simple modifications of existing antiretroviral therapeutics may simultaneously promote an extended-release mechanism and improve unfavorable pharmacokinetic parameters to combat poor patient adherence. We propose to explore the use of glyoxal for generating NRTI prodrugs that undergo spontaneous self-activation over hours to days, providing a mechanism for extended release. Glyoxal reacts with the nucleobases found in many NRTIs, and thus this approach is potentially generalizable to many FDA-approved drugs. Using a diverse NRTI library, we are exploring the substrate scope and kinetics for caging and subsequent activation, and investigating the pharmacokinetic properties of the most promising caged molecules. Together, the work presented here may provide a highly versatile method for achieving timed-release activation of structurally diverse NRTIs, which is anticipated to advance treatment options for patients receiving antiretroviral therapies.

Table of Contents

1 Introduction 1

1.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.2 Nucleoside Reverse Transcriptase Inhibitors . . . . . . . . . . . . . . 4

1.3 Glyoxal Caging of Nucleobases . . . . . . . . . . . . . . . . . . . . . . 7

2 Glyoxal-caging of Nucleoside Reverse Transciptase Inhibitors 9

2.1 Glyoxal-Caging Optimization . . . . . . . . . . . . . . . . . . . . . . 9

2.2 Substrate Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

2.3 Caged-NRTI Purification . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.4 In-vitro De-caging Kinetic Study . . . . . . . . . . . . . . . . . . . . 17

2.5 Enhancement of Solubility and Permeability . . . . . . . . . . . . . . 19

2.6 Future Development . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

2.6.1 Nucleobase Caging with Glyoxal Derivatives . . . . . . . . . . 20

2.6.2 Pharmacokinetic Studies . . . . . . . . . . . . . . . . . . . . . 24

2.6.3 Cellular Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . 25

2.6.4 Anti-Viral Activity . . . . . . . . . . . . . . . . . . . . . . . . 25

2.7 Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . 26

2.7.1 Experimental Overview . . . . . . . . . . . . . . . . . . . . . . 26

2.7.2 General Method to Generate Caged NRTIs . . . . . . . . . . . 27

3 Conclusions 28

3.1 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Appendix A Omitted Data from Chapter 1 31

Appendix B Omitted Data from Chapter 2 33

Bibliography 35

About this Master's Thesis

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School	Laney Graduate School
Department	Chemistry
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Chemistry, Organic
Keyword	Extended-Release Antiviral NRTI
Committee Chair / Thesis Advisor	Jennifer Heemstra, Emory University
Committee Members	Frank McDonald, Emory University Monika Raj, Emory University

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