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J Drug Des Res. 2018;5(2). pii: 1070. Epub 2018 Aug 13.

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

Author information

1
Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, USA.
2
Department of Pediatrics, Infectious Diseases, Emory University, USA.
3
Department of Infectious Disease Research, Southern Research Institute, USA.

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.

KEYWORDS:

Antiviral; Bioisosteres; Computer-aided drug design; HIV-1 capsid protein; Surface plasmon resonance

PMID:
30393786
PMCID:
PMC6214487

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