Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action.

• Type of Material: Article
• Authors: Jimmy P. Xu, Drexel University; Ashwanth Francis, Emory University; Megan E. Meuser, Drexel University; Marie Mankowski, Emory University; Roger G. Ptak, Emory University; Adel A. Rashad, Drexel University; Gregory Melikian, Emory University; Simon Cocklin, Drexel University
• Language: English
• Date: 2018
• Publisher: JSciMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Cocklin et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): https://www.jscimedcentral.com/DrugDesign/drugdesign-5-1070.pdf
• Title of Journal or Parent Work: Journal of Drug Design and Research
• Volume: 5
• Issue: 2
• Grant/Funding Information: This work was supported by NIH/NIAID grant 1 R56 AI118415-01A1 (Cocklin, PI) and R01 GM054787 (Melikian, PI).
• Keywords: HIV-1 capsid protein; Surface plasmon resonance; Antiviral; Computer-aided drug design; Bioisosteres
• Research Categories: Chemistry, Biochemistry; Biology, Molecular

Abstract

Recent efforts by both academic and pharmaceutical researchers have focused on the HIV-1 capsid (CA) protein as a new therapeutic target. An interprotomer pocket within the hexamer configuration of the CA, which is also a binding site for key host dependency factors, is the target of the most widely studied CA inhibitor compound PF-3450074 (PF-74). Despite its popularity, PF-74 suffers from properties that limit its usefulness as a lead, most notably it's extremely poor metabolic stability. To minimize unfavorable qualities, we investigated bioisosteric modification of the PF-74 scaffold as a first step in redeveloping this compound. Using a field-based bioisostere identification method, coupled with biochemical and biological assessment, we have created four new compounds that inhibit HIV-1 infection and that bind to the assembled CA hexamer. Detailed mechanism of action studies indicates that the modifications alter the manner in which these new compounds affect HIV-1 capsid core stability, as compared to the parental compound. Further investigations are underway to redevelop these compounds to optimize potency and drug-like characteristics and to deeply define the mechanism of action.