5KAO

Crystal structure of wild type HIV-1 protease in complex with GRL-10413

5KAO の概要

• エントリーDOI: 10.2210/pdb5kao/pdb
• 関連するPDBエントリー: 4HLA
• 分子名称: protease, [(3~{a}~{S},4~{R},6~{a}~{R})-2,3,3~{a},4,5,6~{a}-hexahydrofuro[2,3-b]furan-4-yl] ~{N}-[(2~{S},3~{R})-1-(3-chloranyl-4-methoxy-phenyl)-4-[(4-methoxyphenyl)sulfonyl-(2-methylpropyl)amino]-3-oxidanyl-butan-2-yl]carbamate (3 entities in total)
• 機能のキーワード: grl-10413, hiv-1 protease, protease-inhibitor, darunavir, 2-chloroanisole, nonpeptidic, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22078.34

構造登録者

Yedidi, R.S.,Delino, N.S.,Das, D.,Kaufman, J.D.,Wingfield, P.T.,Ghosh, A.K.,Mitsuya, H. (登録日: 2016-06-01, 公開日: 2016-08-31, 最終更新日: 2023-09-27)

主引用文献

Amano, M.,Salcedo-Gomez, P.M.,Zhao, R.,Yedidi, R.S.,Das, D.,Bulut, H.,Delino, N.S.,Sheri, V.R.,Ghosh, A.K.,Mitsuya, H.
A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413.
Antimicrob.Agents Chemother., 60:7046-7059, 2016

PubMed Abstract: We report here that GRL-10413, a novel nonpeptidic HIV-1 protease inhibitor (PI) containing a modified P1 moiety and a hydroxyethylamine sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC] of 0.00035 to 0.0018 μM), with minimal cytotoxicity (50% cytotoxic concentration [CC] = 35.7 μM). GRL-10413 blocked the infectivity and replication of HIV-1 variants selected by use of atazanavir, lopinavir, or amprenavir (APV) at concentrations of up to 5 μM (EC = 0.0021 to 0.0023 μM). GRL-10413 also maintained its strong antiviral activity against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to various antiviral regimens after long-term antiretroviral therapy. The development of resistance against GRL-10413 was significantly delayed compared to that against APV. In addition, GRL-10413 showed favorable central nervous system (CNS) penetration properties as assessed with an in vitro blood-brain barrier (BBB) reconstruction system. Analysis of the crystal structure of HIV-1 protease in complex with GRL-10413 demonstrated that the modified P1 moiety of GRL-10413 has a greater hydrophobic surface area and makes greater van der Waals contacts with active site amino acids of protease than in the case of darunavir. Moreover, the chlorine substituent in the P1 moiety interacts with protease in two distinct configurations. The present data demonstrate that GRL-10413 has desirable features for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants, with favorable CNS penetration capability, and that the newly modified P1 moiety may confer desirable features in designing novel anti-HIV-1 PIs.

PubMed: 27620483
DOI: 10.1128/AAC.01428-16

実験手法

X-RAY DIFFRACTION (1.8 Å)