Novel PF74-like small molecules targeting the HIV-1 capsid protein: Balance of potency and metabolic stability.
10.1016/j.apsb.2020.07.016
- Author:
Lei WANG
1
;
Mary C CASEY
2
;
Sanjeev Kumar V VERNEKAR
1
;
Rajkumar Lalji SAHANI
1
;
Karen A KIRBY
3
;
Haijuan DU
3
;
Huanchun ZHANG
3
;
Philip R TEDBURY
3
;
Jiashu XIE
1
;
Stefan G SARAFIANOS
3
;
Zhengqiang WANG
1
Author Information
1. Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
2. Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA.
3. Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
- Publication Type:Journal Article
- Keywords:
ART, antiretroviral therapy;
CA, capsid protein;
CACTD, CA C-terminal domain;
CANTD, CA N-terminal domain;
Capsid protein;
HBA, H-bond acceptor;
HBD, H-bond donor;
HIV, human immunodeficiency virus;
HIV-1;
HLM, human liver microsome;
MLM, mouse liver microsome;
Microsomal stability;
PF74;
PK, pharmacokinetic;
SAR, structure‒activity relationship;
TSA, thermal shift assay
- From:
Acta Pharmaceutica Sinica B
2021;11(3):810-822
- CountryChina
- Language:English
-
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 (
