Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules

• Published in: Viruses Vol. 12; no. 4; p. 452
• Main Authors: Vernekar, Sanjeev Kumar V, Sahani, Rajkumar Lalji, Casey, Mary C, Kankanala, Jayakanth, Wang, Lei, Kirby, Karen A, Du, Haijuan, Zhang, Huanchun, Tedbury, Philip R, Xie, Jiashu, Sarafianos, Stefan G, Wang, Zhengqiang
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16-04-2020; MDPI
• Subjects: Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antiviral agents; Binding Sites; Capsid - chemistry; Capsid - drug effects; Capsid - metabolism; capsid-targeting antivirals; HIV; HIV-1; HIV-1 - drug effects; HIV-1 - metabolism; Humans; metabolic stability; Models, Molecular; Molecular Structure; Molecular targeted therapy; PF74; Physiological aspects; Product development; Protein Binding; Structure-Activity Relationship; Viral proteins; Viral research; Virus Replication - drug effects; United States; HIV-1; capsid-targeting antivirals; PF74; metabolic stability
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v12040452

HIV-1 capsid protein (CA) plays an important role in many steps of viral replication and represents an appealing antiviral target. Several CA-targeting small molecules of various chemotypes have been studied, but the peptidomimetic
has drawn particular interest due to its potent antiviral activity, well-characterized binding mode, and unique mechanism of action. Importantly,
competes against important host factors for binding, conferring highly desirable antiviral phenotypes. However, further development of
is hindered by its prohibitively poor metabolic stability, which necessitates the search for structurally novel and metabolically stable chemotypes. We have conducted a pharmacophore-based shape similarity search for compounds mimicking
. We report herein the analog synthesis and structure-activity relationship (SAR) of two hits from the search, and a third hit designed via molecular hybridization. All analogs were characterized for their effect on CA hexamer stability, antiviral activity, and cytotoxicity. These assays identified three active compounds that moderately stabilize CA hexamer and inhibit HIV-1. The most potent analog (
) inhibited HIV-1 comparably to
but demonstrated drastically improved metabolic stability in liver microsomes (31 min vs. 0.7 min t
). Collectively, the current studies identified a structurally novel and metabolically stable
-like chemotype for targeting HIV-1 CA.