Toward structurally novel and metabolically stable HIV-1 capsid-targeting small molecules

Sanjeev Kumar V. Vernekar, Rajkumar Lalji Sahani, Mary C. Casey, Jayakanth Kankanala, Lei Wang, Karen A. Kirby, Haijuan Du, Huanchun Zhang, Philip R. Tedbury, Jiashu Xie, Stefan G. Sarafianos, Zhengqiang Wang

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish (US)
Article number452
Issue number4
StatePublished - Apr 2020

Bibliographical note

Funding Information:
Funding: 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).

Publisher Copyright:
© 2020 by the authors.


  • Capsid-targeting antivirals
  • HIV-1
  • Metabolic stability
  • PF74


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