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Title: Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants

Abstract

Herein we report the design, synthesis, X–ray structural, and biological studies of an exceptionally potent HIV–1 protease inhibitor, compound 5 ((3S,7aS,8S)–hexahydro–4H–3,5–methanofuro[2,3–b]pyran–8–yl ((2S,3R)–4–((2–(cyclopropylamino)–N–isobutylbenzo[d]thiazole)–6–sulfonamido)–1–(3,5–difluorophenyl)–3–hydroxybutan–2–yl)carbamate). Using structure–based design, we incorporated an unprecedented 6–5–5–ring–fused crown–like tetrahydropyranofuran as the P2–ligand, a cyclopropylaminobenzothiazole as the P2'–igand, and a 3,5–difluorophenylmethyl group as the P1–ligand. The resulting inhibitor 5 exhibited exceptional HIV–1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC50 values in the picomolar range against a wide panel of highly multidrug–resistant HIV–1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug…resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. Here, we determined a high–resolution X–ray crystal structure of the complex between inhibitor 5 and HIV–1 protease, which provides molecular insight into the unprecedented activity profiles observed.

Authors:
ORCiD logo [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3];  [4];  [2];  [3]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. School of Medicine (Japan); National Cancer Inst., Bethesda, MD (United States); National Center for Global Heath and Medicine, Tokyo (Japan)
  4. National Center for Global Heath and Medicine, Tokyo (Japan)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Inst. of General Medical Sciences; National Inst. of Health
OSTI Identifier:
1435833
Grant/Contract Number:  
GM53386; GM62920
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
ChemMedChem(Print)
Additional Journal Information:
Journal Volume: 13; Journal Issue: 8; Journal ID: ISSN 1860-7179
Publisher:
ChemPubSoc Europe
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; antiviral agents; brain penetration; drug resistance; HIV-1 protease; structure-based design

Citation Formats

Ghosh, Arun K., Rao, Kalapala Venkateswara, Nyalapatla, Prasanth R., Kovela, Satish, Brindisi, Margherita, Osswald, Heather L., Reddy, Bhavanam Sekhara , Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Hattori, Shin-ichiro, Weber, Irene T., and Mitsuya, Hiroaki. Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants. United States: N. p., 2018. Web. doi:10.1002/cmdc.201700824.
Ghosh, Arun K., Rao, Kalapala Venkateswara, Nyalapatla, Prasanth R., Kovela, Satish, Brindisi, Margherita, Osswald, Heather L., Reddy, Bhavanam Sekhara , Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Hattori, Shin-ichiro, Weber, Irene T., & Mitsuya, Hiroaki. Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants. United States. doi:10.1002/cmdc.201700824.
Ghosh, Arun K., Rao, Kalapala Venkateswara, Nyalapatla, Prasanth R., Kovela, Satish, Brindisi, Margherita, Osswald, Heather L., Reddy, Bhavanam Sekhara , Agniswamy, Johnson, Wang, Yuan-Fang, Aoki, Manabu, Hattori, Shin-ichiro, Weber, Irene T., and Mitsuya, Hiroaki. Tue . "Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants". United States. doi:10.1002/cmdc.201700824. https://www.osti.gov/servlets/purl/1435833.
@article{osti_1435833,
title = {Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants},
author = {Ghosh, Arun K. and Rao, Kalapala Venkateswara and Nyalapatla, Prasanth R. and Kovela, Satish and Brindisi, Margherita and Osswald, Heather L. and Reddy, Bhavanam Sekhara  and Agniswamy, Johnson and Wang, Yuan-Fang and Aoki, Manabu and Hattori, Shin-ichiro and Weber, Irene T. and Mitsuya, Hiroaki},
abstractNote = {Herein we report the design, synthesis, X–ray structural, and biological studies of an exceptionally potent HIV–1 protease inhibitor, compound 5 ((3S,7aS,8S)–hexahydro–4H–3,5–methanofuro[2,3–b]pyran–8–yl ((2S,3R)–4–((2–(cyclopropylamino)–N–isobutylbenzo[d]thiazole)–6–sulfonamido)–1–(3,5–difluorophenyl)–3–hydroxybutan–2–yl)carbamate). Using structure–based design, we incorporated an unprecedented 6–5–5–ring–fused crown–like tetrahydropyranofuran as the P2–ligand, a cyclopropylaminobenzothiazole as the P2'–igand, and a 3,5–difluorophenylmethyl group as the P1–ligand. The resulting inhibitor 5 exhibited exceptional HIV–1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC50 values in the picomolar range against a wide panel of highly multidrug–resistant HIV–1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug…resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. Here, we determined a high–resolution X–ray crystal structure of the complex between inhibitor 5 and HIV–1 protease, which provides molecular insight into the unprecedented activity profiles observed.},
doi = {10.1002/cmdc.201700824},
journal = {ChemMedChem(Print)},
issn = {1860-7179},
number = 8,
volume = 13,
place = {United States},
year = {2018},
month = {2}
}

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Cited by: 11 works
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