Novel PF74-like small molecules targeting the HIV-1 capsid protein: balance of potency and metabolic stability

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

Research output: Contribution to journalArticlepeer-review


Of all known small molecules targeting human immunodeficiency virus (HIV) capsid protein (CA), PF74 represents by far the best characterized chemotype, due to its ability to confer antiviral phenotypes in both early and late phases of viral replication. However, the prohibitively low metabolic stability renders PF74 a poor antiviral lead. We report herein our medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding site. Specifically, we replaced the inter-domain-interacting, electron-rich indole ring of PF74 with less electron-rich isosteres, including imidazolidine-2,4-dione, pyrimidine-2,4-dione, and benzamide, and identified four potent antiviral compounds (10, 19, 20 and 26) with markedly improved metabolic stability. Compared to PF74, analog 20 exhibited similar submicromolar potency, and much longer (51-fold) half-life in human liver microsomes (HLMs). Molecular docking corroborated that 20 binds to the PF74 binding site, and revealed distinct binding interactions conferred by the benzamide moiety. Collectively, our data support compound 20 as a promising antiviral lead.

Original languageEnglish (US)
JournalActa Pharmaceutica Sinica B
StateAccepted/In press - 2020

Bibliographical note

Funding Information:
This research was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health , USA, grant number R01AI120860 (to Stefan G. Sarafianos and Zhengqiang Wang). We thank the Minnesota Supercomputing Institute (Minneapolis, MN, USA) for molecular modeling resources.


  • Capsid protein
  • HIV-1
  • Microsomal stability
  • PF74

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