Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies

Ghosh, Arun K.; Xia, Zilei; Kovela, Satish; Robinson, William L.; Johnson, Megan E.; Kneller, Daniel W.; Wang, Yuan‐Fang; Aoki, Manabu; Takamatsu, Yuki; Weber, Irene T.; Mitsuya, Hiroaki

doi:10.1002/cmdc.201900508

Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies

Journal Article · Fri Oct 04 00:00:00 EDT 2019 · ChemMedChem

DOI:https://doi.org/10.1002/cmdc.201900508· OSTI ID:1577162

^[1]; Xia, Zilei ^[1]; Kovela, Satish ^[1]; Robinson, William L. ^[1]; Johnson, Megan E. ^[1]; Kneller, Daniel W. ^[2]; Wang, Yuan‐Fang ^[2]; Aoki, Manabu ^[3]; Takamatsu, Yuki ^[4]; Weber, Irene T. ^[2]; Mitsuya, Hiroaki ^[5]

Purdue Univ., West Lafayette, IN (United States)
Georgia State Univ., Atlanta, GA (United States)
National Cancer Inst., Bethesda, MD (United States); National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
Kumamoto Univ. (Japan); National Cancer Inst., Bethesda, MD (United States); National Center for Global Health and Medicine Research Inst., Tokyo (Japan)

We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. Inhibitors bearing bis-THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2' ligands, showed very potent HIV-1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide-derived inhibitors which showed good antiviral IC₅₀ value. Boronic acid derived inhibitor with bis-THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2-Crn-THF ligand also showed potent enzyme K_i but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug-resistant HIV-1 variants. One of the inhibitors maintained good antiviral activity against HIV_DRV^R_P20 and HIV_DRV^R_P30 viruses. We have determined high resolution X-ray structures of two synthetic inhibitors bound to HIV-1 protease and obtained molecular insight into the ligand-binding site interactions.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: Japan Agency for Medical Research and Development (AMED); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1577162

Journal Information:: ChemMedChem, Journal Name: ChemMedChem Journal Issue: 21 Vol. 14; ISSN 1860-7179

Publisher:: ChemPubSoc EuropeCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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