Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants.
Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants.
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DOI：
10.1002/cmdc.201700824
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发表时间：
2018-04-23
期刊：
影响因子：
3.4
通讯作者：
Mitsuya H
中科院分区：
文献类型：
--
作者：
Ghosh AK;Rao KV;Nyalapatla PR;Kovela S;Brindisi M;Osswald HL;Sekhara Reddy B;Agniswamy J;Wang YF;Aoki M;Hattori SI;Weber IT;Mitsuya H
本文报道了一种特别有效的HIV-1蛋白酶抑制剂化合物5 ((3S,7aS,8S)-六氢- 4h -3,5-甲烷ofuro[2,3-b]吡喃-8-基（（2S,3R)-4-（（2-（环丙基氨基）- n-异丁基苯并[d]噻唑）-6-磺胺）-1-（3,5-二氟苯基）-3-羟基丁烷-2-基）氨基甲酸酯）的设计、合成、x射线结构和生物学研究。采用基于结构的设计，我们史无前例地将6-5-5环融合的冠状四氢吡喃作为P2配体，环丙基苯并噻唑作为P2 '配体，3,5-二氟苯基甲基作为p1配体。由此产生的抑制剂5在皮摩尔水平上表现出异常的HIV-1蛋白酶抑制和抗病毒效力。此外，它显示抗病毒IC50值在皮摩尔范围内对广泛的高度多药耐药的HIV-1变异。该抑制剂对耐药变异的出现显示出极高的遗传屏障。它还表现出极强的抑制二聚化的活性，并有利于中枢神经系统的渗透。我们确定了抑制剂5和HIV-1蛋白酶之间复合物的高分辨率x射线晶体结构，这为观察到的前所未有的活性谱提供了分子洞察力。清晰：我们报道了一系列特别有效的HIV-1蛋白酶抑制剂的基于结构的设计，合成，生物学评价和x射线结构研究，这些抑制剂含有新的P1， P2和P2 '配体，可以与活性位点残基相互作用。抑制剂5在皮摩尔水平显示出特殊的HIV-1抑制和抗病毒效力。抑制剂5结合HIV-1蛋白酶复合物的x射线结构为前所未有的活性谱提供了分子洞察力。
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 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. 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. Crystal clear: We report the structure-based design, synthesis, biological evaluation, and X-ray structural studies of a series of exceptionally potent HIV-1 protease inhibitors containing novel P1, P2, and P2′ ligands to interact with active site residues. Inhibitor 5 shows exceptional HIV-1 inhibitory and antiviral potency at the picomolar level. An X-ray structure of the inhibitor 5-bound HIV-1 protease complex provides molecular insight into the unprecedented activity profiles.
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影响因子：
7.3
作者：
Ghosh AK;Osswald HL;Prato G
通讯作者：
Prato G
影响因子：
3.4
作者：
Ghosh, Arun K.;Yashchuk, Sofiya;Mizuno, Akira;Chakraborty, Nilanjana;Agniswamy, Johnson;Wang, Yuan-Fang;Aoki, Manabu;Gomez, Pedro Miguel Salcedo;Amano, Masayuki;Weber, Irene T.;Mitsuya, Hiroaki
通讯作者：
Mitsuya, Hiroaki
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
15
作者：
GAO, Y;HANSON, RM;SHARPLESS, KB
通讯作者：
SHARPLESS, KB
影响因子：
3.6
作者：
Ghosh, AK;Leshchenko, S;Noetzel, M
通讯作者：
Noetzel, M