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.

Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants / 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. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 13:8(2018), pp. 803-815. [10.1002/cmdc.201700824]

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

Brindisi, Margherita;
2018

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'-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.
2018
Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants / 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. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 13:8(2018), pp. 803-815. [10.1002/cmdc.201700824]
File in questo prodotto:
File Dimensione Formato  
Design of Highly Potent, Dual‐Acting and Central‐Nervous‐System‐Penetrating HIV‐1 Protease Inhibitors.pdf

non disponibili

Dimensione 1.09 MB
Formato Adobe PDF
1.09 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/771147
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 36
  • ???jsp.display-item.citation.isi??? 33
social impact