Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies
Abstract
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 Ki 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 HIVDRVRP20 and HIVDRVRP30 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.
- Authors:
-
[1];
- 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)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); Japan Agency for Medical Research and Development (AMED)
- OSTI Identifier:
- 1577162
- Grant/Contract Number:
- AI150466; AI150461; R01AI121315; JP15fk0410001; JP18fk0410001; W-31-109-ENG-38
- Resource Type:
- Accepted Manuscript
- Journal Name:
- ChemMedChem
- Additional Journal Information:
- Journal Volume: 14; Journal Issue: 21; Journal ID: ISSN 1860-7179
- Publisher:
- ChemPubSoc Europe
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; brain penetration; drug resistance; genetic barriers; HIV-1 protease inhibitors; structure-based design
Citation Formats
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., and Mitsuya, Hiroaki. Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies. United States: N. p., 2019.
Web. doi:10.1002/cmdc.201900508.
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. Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies. United States. https://doi.org/10.1002/cmdc.201900508
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., and Mitsuya, Hiroaki. Fri .
"Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies". United States. https://doi.org/10.1002/cmdc.201900508. https://www.osti.gov/servlets/purl/1577162.
@article{osti_1577162,
title = {Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies},
author = {Ghosh, Arun K. and Xia, Zilei and Kovela, Satish and Robinson, William L. and Johnson, Megan E. and Kneller, Daniel W. and Wang, Yuan‐Fang and Aoki, Manabu and Takamatsu, Yuki and Weber, Irene T. and Mitsuya, Hiroaki},
abstractNote = {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 Ki 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 HIVDRVRP20 and HIVDRVRP30 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.},
doi = {10.1002/cmdc.201900508},
journal = {ChemMedChem},
number = 21,
volume = 14,
place = {United States},
year = {Fri Oct 04 00:00:00 EDT 2019},
month = {Fri Oct 04 00:00:00 EDT 2019}
}
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