Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Jorgensen, William
Abstract
The HIV/AIDS crisis remains a major world health problem, particularly in under-developed countries. Though advancements made in highly active retroviral therapy (HAART) in recent years have significantly reduced the annual deaths, the emergence of problematic mutant variants, coupled with issues of dosing, pill burden, and compliance, have necessitated the continued improvement of these therapeutics. Diversifying the scaffolds of non-nucleoside reverse transcriptase inhibitors (NNRTIs) used in combination therapy has the benefit of overwhelming the virion and raising the genetic barrier to resistance-associated mutations (RAMs). Additionally, the emergence of covalent RT inhibitors (CRTIs) opens the possibility of complete, irreversible eradication of the RT protein. Both of these strategies are presented in this thesis, through a combination of computational modeling, synthetic chemistry, and biological assays. Building off of previous work in designing a covalent inhibitor targeting the problematic Y181C mutant, the first ever covalent inhibitors targeting wild-type HIV-1 RT are reported here. Using a catechol diether scaffold and installing a fluorosulfate warhead to target Tyr181, the WT RT protein is modified by three such compounds. Covalent modification was confirmed through X-ray crystallography and mass spectrometry. Having successfully targeted a tyrosine in the NNRTI binding site, attention was turned to Tyr188, where a previously reported benzyloxazole scaffold was employed. Multiple biphenyl oxazoles were synthesized and assayed in this series. Though novel, potent NNRTIs were developed in this effort, there was no evidence of covalent binding. A crystal structure was obtained for a previously synthesized benzyl oxazole, opening the door to future computational modeling to guide new synthesis. Finally, the less explored lysine residue Lys102 was targeted. Using both catechol and resorcinol diether scaffolds, several warheads were tested, including acrylamide and -haloamide for Michael additions and sulfonyl fluorides for addition-elimination reactions. While there is not yet evidence of covalent inhibition, we currently have several analogues with low-nanomolar binding. X-ray crystal structures were also obtained for a few of these compounds, and continued computational and synthetic efforts will focus on elucidating a structure-activity relationship and delivering the warhead to the amino acid residue of interest.
Recommended Citation
Carter, Zachary, "Discovery of Novel Covalent and Non-Covalent Inhibitors of HIV-1 Reverse Transcriptase" (2022). Yale Graduate School of Arts and Sciences Dissertations. 719.
https://elischolar.library.yale.edu/gsas_dissertations/719
