Date of Award

Spring 5-2019

Degree Type

Honors College Thesis

Department

Biological Sciences

First Advisor

Jacques Kessl

Advisor Department

Biological Sciences

Abstract

Human Immunodeficiency Virus Type 1 (HIV-1), a single stranded RNA retrovirus, affects over 30,000,000 people world-wide1. The virus works by infecting and promoting destruction of CD4 immune cells. and thus, suppressing proper immune functions2. Contrary to DNA viruses, the absence of extensive proofreading mechanisms in RNA viruses makes HIV latency a major obstacle in the discovery of long-term, effective treatments. Moreover, the importance of exploring novel therapeutic targets and designing complimentary inhibitory molecules remains steadfast in HIV research3 Recently, HIV-1 Integrase (IN) multimerization, the core enzyme used for integration of the viral DNA into an invaded host chromosome, has been identified as an unexploited therapeutic target. Moreover, a class of quinoline based allosteric integrase inhibitors (ALLINs) have shown promising inhibitory effects, most notably in the assembly of inactive viral particles 4. The exact mechanism of action of this class of molecules, however, remains unclear due to the multimodal role of the drug. Herein, we report potencies of six synthesized single point derivatives of 4-phenylquinoline using an innovative in vitro assay capable of measuring the multimerization between full length IN and constructed C-terminal domain (CTD) using Fluorescence Resonance Energy Transfer (FRET) and antibody-conjugated fluorophores. The potencies of IN multimerizing drugs were characterized by their EC50 values obtained from the drug concentration vs FRET curve. Our results, complimentary to recent studies, support the proposed mechanism of action of this class of ALLINs and highlight the antiviral potential of improved quinoline-based molecule derivatives to further exploit HIV-1 IN v multimerization as a therapeutic target

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