TY - JOUR
T1 - Novel PF74-like small molecules targeting the HIV-1 capsid protein
T2 - balance of potency and metabolic stability
AU - Wang, Lei
AU - Casey, Mary C.
AU - Vernekar, Sanjeev Kumar V
AU - Sahani, Rajkumar Lalji
AU - Kirby, Karen A.
AU - Du, Haijuan
AU - Zhang, Huanchun
AU - Tedbury, Philip R.
AU - Xie, Jiashu
AU - Sarafianos, Stefan G.
AU - Wang, Zhengqiang
N1 - 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.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Capsid protein
KW - HIV-1
KW - Microsomal stability
KW - PF74
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U2 - 10.1016/j.apsb.2020.07.016
DO - 10.1016/j.apsb.2020.07.016
M3 - Article
AN - SCOPUS:85094600482
JO - Acta Pharmaceutica Sinica B
JF - Acta Pharmaceutica Sinica B
SN - 2211-3835
ER -