Original articles
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. Novel PF74-like small molecules targeting the HIV-1 capsid protein: Balance of potency and metabolic stability[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 810-822

Novel PF74-like small molecules targeting the HIV-1 capsid protein: Balance of potency and metabolic stability
Lei Wanga,d, Mary C. Caseyb, Sanjeev Kumar V. Vernekara, Rajkumar Lalji Sahania, Karen A. Kirbyc, Haijuan Duc, Huanchun Zhangc, Philip R. Tedburyc, Jiashu Xiea, Stefan G. Sarafianosc, Zhengqiang Wanga
a Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA;
b Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA;
c Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA;
d Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
Abstract:
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.
Key words:    HIV-1    Capsid protein    PF74    Microsomal stability   
Received: 2020-06-17     Revised: 2020-07-08
DOI: 10.1016/j.apsb.2020.07.016
Funds: 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.
Corresponding author: Zhengqiang Wang     Email:wangx472@umn.edu
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Authors
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

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