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

• Type of Material: Article
• Authors: Sanjeev Kumar V. Vernekar, University of Minnesota; Rajkumar Lalji Sahani, University of Minnesota; Mary C. Casey, University of Missouri; Jayakanth Kankanala, University of Minnesota; Lei Wang, University of Minnesota; Karen Kirby, Emory University; Haijuan Du, Emory University; Huanchun Zhang, Emory University; Philip Tedbury, Emory University; Jiashu Xie, University of Minnesota; Stefan Sarafianos, Emory University; Zhengqiang Wang, University of Minnesota
• Language: English
• Date: 2020-04-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/v12040452
• Title of Journal or Parent Work: VIRUSES-BASEL
• Volume: 12
• Issue: 4
• Grant/Funding Information: This research was funded by the National Institute of Allergy and Infectious Diseases, the National Institute of Health, grant number R01AI120860 (to SGS and ZW).
• Keywords: metabolic stability; INFECTION; DISCOVERY; PF74; Virology; HIV-1; Life Sciences & Biomedicine; REPLICATION; Science & Technology; CYCLOPHILIN-A; POTENT; PROTEIN; ROLES; THERMAL SHIFT ASSAYS; MODEL; capsid-targeting antivirals; INHIBITION
• Research Categories: Health Sciences, Pharmacology; Biology, Virology

Abstract

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 PF74 has drawn particular interest due to its potent antiviral activity, well-characterized binding mode, and unique mechanism of action. Importantly, PF74 competes against important host factors for binding, conferring highly desirable antiviral phenotypes. However, further development of PF74 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 PF74. 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 (10) inhibited HIV-1 comparably to PF74 but demonstrated drastically improved metabolic stability in liver microsomes (31 min vs. 0.7 min t1/2). Collectively, the current studies identified a structurally novel and metabolically stable PF74-like chemotype for targeting HIV-1 CA.