Chemical profiling of HIV-1 capsid-targeting antiviral PF74.

We report herein the design, synthesis, and evaluation of a large number of PF74 analogs aiming to provide a comprehensive chemical profiling of PF74 and advance the understanding on its detailed binding mechanism and pharmacophore. The analogs, containing structural variations mainly in the aniline domain and/or the indole domain, were assayed for their effect on stability of CA hexamers, antiviral activity, and cytotoxicity. Selected analogs were also tested for metabolic stability in liver microsomes, alone or in the presence of a CYP3A inhibitor. Collectively, our studies identified important pharmacophore elements and revealed additional binding features of PF74, which could aid in future design of improved ligands to better probe the molecular basis of CA-host factor interactions, design strategies to disrupt them, and ultimately identify viable CA-targeting antiviral leads.
PMID: 32438252 [PubMed - as supplied by publisher]

Source: European Journal of Medicinal Chemistry - May 11, 2020 Category: Chemistry Authors: Wang L, Casey MC, Vernekar SKV, Do HT, Sahani RL, Kirby KA, Du H, Hachiya A, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z Tags: Eur J Med Chem Source Type: research