Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants.
Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants.
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DOI：
10.1021/acs.jmedchem.7b00172
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发表时间：
2017-05-25
影响因子：
7.3
通讯作者：
Mitsuya H
中科院分区：
文献类型：
--
作者：
Ghosh AK;Rao KV;Nyalapatla PR;Osswald HL;Martyr CD;Aoki M;Hayashi H;Agniswamy J;Wang YF;Bulut H;Das D;Weber IT;Mitsuya H
设计，合成和评价一类新的异常有效的HIV-1蛋白酶抑制剂的报告。抑制剂5显示出上级的抗病毒活性和耐药性。事实上，这种抑制剂显示出比FDA批准的药物达芦那韦提高几个数量级的抗病毒活性。该抑制剂结合了前所未有的6-5-5环稠合冠状四氢吡喃并呋喃作为P2配体和氨基苯并噻唑作为P2′配体与（R）-羟乙基磺酰胺等排体。该抑制剂的冠状P2配体已被有效地合成为光学活性形式，使用手性Diels-Alder催化剂，提供高对映体纯度的关键中间体。两个高分辨率的X-射线结构的结合的HIV-1蛋白酶揭示了广泛的相互作用与HIV-1蛋白酶的骨架原子，并提供了这些新的抑制剂的结合特性的分子洞察。
Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors is reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug, darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2′ ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.
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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：
15
作者：
GAO, Y;HANSON, RM;SHARPLESS, KB
通讯作者：
SHARPLESS, KB
影响因子：
3.5
作者：
Ghosh, Arun K.;Dawson, Zachary L.;Mitsuya, Hiroaki
通讯作者：
Mitsuya, Hiroaki
DOI：
10.1016/b978-0-12-397176-0.00013-3
发表时间：
2013-01-01
期刊：
INTRODUCTION TO BIOLOGICAL AND SMALL MOLECULE DRUG RESEARCH AND DEVELOPMENT: THEORY AND CASE STUDIES
影响因子：
--
作者：
Ghosh, Arun K.;Chapsal, Bruno D.
通讯作者：
Chapsal, Bruno D.
影响因子：
5.2
作者：
Ghosh, Arun K.;Chapsal, Bruno D.;Mitsuya, Hiroaki
通讯作者：
Mitsuya, Hiroaki