Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir
Abstract
The structure–based design, synthesis, and biological evaluation of a series of nonpeptidic HIV–1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2' subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2' ligands was set by asymmetric reduction of the corresponding ketone using (R,R)– or (S,S)–Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme Ki values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir–resistant HIV–1 variants. In conclusion, an X–ray structure of inhibitor 3g in complex with HIV–1 protease revealed key interactions in the S2' subsite.
- Authors:
-
[1];
- Purdue Univ., West Lafayette, IN (United States)
- Georgia State Univ., Atlanta, GA (United States)
- Kumamoto Univ. School of Medicine (Japan)
- Kumamoto Univ. School of Medicine (Japan) ; National Cancer Inst., Bethesda, MD (United States); National Center for Global Heath and Medicine, Tokyo (Japan)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Inst. of Health
- OSTI Identifier:
- 1422231
- Grant/Contract Number:
- 053386; GM53386; GM62920
- Resource Type:
- Accepted Manuscript
- Journal Name:
- ChemMedChem
- Additional Journal Information:
- Journal Volume: 12; Journal Issue: 23; Journal ID: ISSN 1860-7179
- Publisher:
- ChemPubSoc Europe
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; drug resistance; HIV-1 protease inhibitors; P2′ ligands; pharmacokinetics; structure-based design
Citation Formats
Ghosh, Arun K., Fyvie, W. Sean, Brindisi, Margherita, Steffey, Melinda, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., and Mitsuya, Hiroaki. Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir. United States: N. p., 2017.
Web. doi:10.1002/cmdc.201700614.
Ghosh, Arun K., Fyvie, W. Sean, Brindisi, Margherita, Steffey, Melinda, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., & Mitsuya, Hiroaki. Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir. United States. https://doi.org/10.1002/cmdc.201700614
Ghosh, Arun K., Fyvie, W. Sean, Brindisi, Margherita, Steffey, Melinda, Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Amano, Masayuki, Weber, Irene T., and Mitsuya, Hiroaki. Mon .
"Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir". United States. https://doi.org/10.1002/cmdc.201700614. https://www.osti.gov/servlets/purl/1422231.
@article{osti_1422231,
title = {Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir},
author = {Ghosh, Arun K. and Fyvie, W. Sean and Brindisi, Margherita and Steffey, Melinda and Agniswamy, Johnson and Wang, Yuan-Fang and Aoki, Manabu and Amano, Masayuki and Weber, Irene T. and Mitsuya, Hiroaki},
abstractNote = {The structure–based design, synthesis, and biological evaluation of a series of nonpeptidic HIV–1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2' subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2' ligands was set by asymmetric reduction of the corresponding ketone using (R,R)– or (S,S)–Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme Ki values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir–resistant HIV–1 variants. In conclusion, an X–ray structure of inhibitor 3g in complex with HIV–1 protease revealed key interactions in the S2' subsite.},
doi = {10.1002/cmdc.201700614},
journal = {ChemMedChem},
number = 23,
volume = 12,
place = {United States},
year = {Mon Nov 06 00:00:00 EST 2017},
month = {Mon Nov 06 00:00:00 EST 2017}
}
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Works referencing / citing this record:
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, October 2019
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