Date of Award
5-2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
School
Mathematics and Natural Sciences
Committee Chair
Dr. Jacques J. Kessl
Committee Chair School
Mathematics and Natural Sciences
Committee Member 2
Dr. Fengwei Bai
Committee Member 2 School
Biological, Environmental, and Earth Sciences
Committee Member 3
Dr. Matthew G. Donahue
Committee Member 3 School
Mathematics and Natural Sciences
Committee Member 4
Dr. Faqing Huang
Committee Member 4 School
Mathematics and Natural Sciences
Committee Member 5
Dr. Julie A. Pigza
Committee Member 5 School
Mathematics and Natural Sciences
Abstract
The human immunodeficiency virus type 1 (HIV-1) infection remains a global health crisis, necessitating the development of innovative antiviral strategies. During the integration step, HIV-1 integrase (IN) interacts with viral DNA and the cellular cofactor LEDGF/p75 to effectively integrate the reverse transcript into the host chromatin. Recently, a novel class of antiretroviral agents called Allosteric Inhibitors of HIV-1 Integrase (ALLINI) compounds has emerged as a promising avenue in the fight against HIV-1. While originally designed to inhibit IN-LEDGF/p75 interactions, these compounds have been shown to also impact late-stage viral maturation severely through IN multimerization. Induction of IN multimerization interferes with virion maturation through misvocalization of vRNA rendering them noninfectious. ALLINI compounds have shown potent antiviral activity against a broad range of HIV-1 strains, including drug-resistant variants. This abstract provides an overview of the use of the ALLINI compounds based on quinoline scaffold derivatives which have been shown to exhibit enhanced potency, prolonged antiviral activity, and reduced likelihood of resistance. Additionally, this research explores the inclusion of covalent warheads with the aim to optimize these compounds and explore their applications as a part of therapeutic strategies for HIV-1, offering new avenues for effective treatment strategies and their integration into future combination antiretroviral therapies.
ORCID ID
0000-0003-1232-3264
Copyright
Krunal Hiteshkumar Patel, 2024
Recommended Citation
Patel, Krunal H., "Design, Synthesis, and Optimization of Allosteric Inhibitors of HIV-1 Integrase" (2024). Dissertations. 2248.
https://aquila.usm.edu/dissertations/2248
Included in
Biochemistry Commons, Computational Chemistry Commons, Medicinal-Pharmaceutical Chemistry Commons, Organic Chemistry Commons