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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
Authors: Ghosh, Arun K
Rao, Kalapala Venkateswara
Nyalapatla, Prasanth R
Kovela, Satish
Brindisi, Margherita 
Osswald, Heather L
Sekhara Reddy, Bhavanam
Agniswamy, Johnson
Wang, Yuan-Fang
Aoki, Manabu
Hattori, Shin-Ichiro
Weber, Irene T
Mitsuya, Hiroaki
Keywords: HIV-1 protease; antiviral agents; brain penetration; drug resistance; structure-based design
Issue Date: 2018
Project: None 
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'-ligand, 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 IC50values 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. 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.
ISSN: 1860-7179
DOI: 10.1002/cmdc.201700824
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