Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants
Abstract
Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6–5–5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels–Alder catalyst providing a key intermediate in high enantiomeric purity. Furthermore, two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.
- Authors:
-
[1];
[4];
- Purdue Univ., West Lafayette, IN (United States)
- Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); Kumamoto Health Science Univ. (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)
- Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); National Center for Global Health and Medicine Research Inst., Tokyo (Japan)
- Georgia State Univ., Atlanta, GA (United States)
- National Inst. of Health (NIH), Bethesda, MD (United States)
- Kumamoto Univ. Graduate School of Biomedical Sciences (Japan); National Center for Global Health and Medicine Research Inst., Tokyo (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Inst. of Health; Intramural Research Program of the Center for Cancer Research; National Cancer Inst.
- OSTI Identifier:
- 1368286
- Grant/Contract Number:
- GM53386; GM62920; W-31-109-Eng-38
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Volume: 60; Journal Issue: 10; Journal ID: ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Antimicrobial agents; Peptides and proteins; Ligands; Inhibitors; Noncovalent interactions
Citation Formats
Ghosh, Arun K., Rao, Kalapala Venkateswara, Nyalapatla, Prasanth R., Osswald, Heather L., Martyr, Cuthbert D., Aoki, Manabu, Hayashi, Hironori, Agniswamy, Johnson, Wang, Yuan-Fang, Bulut, Haydar, Das, Debananda, Weber, Irene T., and Mitsuya, Hiroaki. Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants. United States: N. p., 2017.
Web. doi:10.1021/acs.jmedchem.7b00172.
Ghosh, Arun K., Rao, Kalapala Venkateswara, Nyalapatla, Prasanth R., Osswald, Heather L., Martyr, Cuthbert D., Aoki, Manabu, Hayashi, Hironori, Agniswamy, Johnson, Wang, Yuan-Fang, Bulut, Haydar, Das, Debananda, Weber, Irene T., & Mitsuya, Hiroaki. Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants. United States. https://doi.org/10.1021/acs.jmedchem.7b00172
Ghosh, Arun K., Rao, Kalapala Venkateswara, Nyalapatla, Prasanth R., Osswald, Heather L., Martyr, Cuthbert D., Aoki, Manabu, Hayashi, Hironori, Agniswamy, Johnson, Wang, Yuan-Fang, Bulut, Haydar, Das, Debananda, Weber, Irene T., and Mitsuya, Hiroaki. Tue .
"Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants". United States. https://doi.org/10.1021/acs.jmedchem.7b00172. https://www.osti.gov/servlets/purl/1368286.
@article{osti_1368286,
title = {Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants},
author = {Ghosh, Arun K. and Rao, Kalapala Venkateswara and Nyalapatla, Prasanth R. and Osswald, Heather L. and Martyr, Cuthbert D. and Aoki, Manabu and Hayashi, Hironori and Agniswamy, Johnson and Wang, Yuan-Fang and Bulut, Haydar and Das, Debananda and Weber, Irene T. and Mitsuya, Hiroaki},
abstractNote = {Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6–5–5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels–Alder catalyst providing a key intermediate in high enantiomeric purity. Furthermore, two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.},
doi = {10.1021/acs.jmedchem.7b00172},
journal = {Journal of Medicinal Chemistry},
number = 10,
volume = 60,
place = {United States},
year = {Tue Apr 18 00:00:00 EDT 2017},
month = {Tue Apr 18 00:00:00 EDT 2017}
}
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