GRL-079, a Novel HIV-1 Protease Inhibitor, Is Extremely Potent against Multidrug-Resistant HIV-1 Variants and Has a High Genetic Barrier against the Emergence of Resistant Variants.
GRL-079, a Novel HIV-1 Protease Inhibitor, Is Extremely Potent against Multidrug-Resistant HIV-1 Variants and Has a High Genetic Barrier against the Emergence of Resistant Variants.
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GRL-079 是一种新型 HIV-1 蛋白酶抑制剂，对多重耐药 HIV-1 变异体非常有效，并且对耐药变异体的出现具有很高的遗传屏障。
DOI：
10.1128/aac.02060-17
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发表时间：
2018
影响因子：
4.9
通讯作者：
Mitsuya,Hiroaki
中科院分区：
文献类型：
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作者：
Delino,NicoleS;Aoki,Manabu;Hayashi,Hironori;Hattori,Shin-Ichiro;Chang,SimonB;Takamatsu,Yuki;Martyr,CuthbertD;Das,Debananda;Ghosh,ArunK;Mitsuya,Hiroaki
我们鉴定了4种新型的非肽类HIV-1蛋白酶抑制剂（PI）GRL-078、-079、-077和-058，它们在P2四氢吡喃四氢呋喃（TP-THF）的C-5位上含有一个烷基胺和一个P2′环丙基（Cp）（或异丙基）氨基苯并噻唑（Abt）基团。它们对野生型HIV-1 NL 4 -3的50%有效浓度（EC 50）为2.5至30 nM，对HIV-2 EHO为0.3至6.7 nM，对实验室选择的PI耐药HIV-1和对多种FDA批准的PI耐药的临床HIV-1变体（HIVMDR）为0.9至90 nM。GRL-078、GRL-079、GRL-077和GRL-058还有效阻断了对达芦那韦（DRV）高度耐药的HIV-1变异体的复制。（HIV DRVrp 51），EC 50分别为38、62、61和90 nM，而FDA批准的四种PI检查（安普那韦、阿扎那韦、洛匹那韦[LPV]和DRV）对HIV DRVrp 51几乎没有活性（EC 50> 1，000 nM）。在结构上，GRL-078、-079和-058在C-5位修饰的Tp-THF与野生型蛋白酶的Asp 29/Asp 30/Gly 48之间形成强氢键作用，而P2′ Cp-Abt基团与Asp 30 ′形成强氢键作用。TP-THF和Cp-Abt部分也具有良好的非极性相互作用与蛋白酶残基位于瓣区。用11株HIVMDR混合株（HIV 11 MIX）进行LPV和DRV选择，HIV 11 MIX分别在13 ~ 32周和32 ~ 41周对LPV和DRV产生高度抗性。然而，对于GRL-079和GRL-058的选择，HIV 11 MIX分别在>0.08 μM和>0.2 μM时不能复制。热稳定性结果支持GRL-079以及其他PI的高度有利的抗HIV-1效力。这些结果表明，P2 Tp-THF基团和P2′ Abt基团是这4种PI对HIV-1 NL 4 - 3和广谱HIV-1 MDR病毒株具有较强抗HIV-1活性的重要原因。
We identified four novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-078, -079, -077, and -058, containing an alkylamine at the C-5 position of P2 tetrahydropyrano-tetrahydrofuran (Tp-THF) and a P2′ cyclopropyl (Cp) (or isopropyl)-aminobenzothiazole (Abt) moiety. Their 50% effective concentrations (EC50s) were 2.5 to 30 nM against wild-type HIV-1NL4-3, 0.3 to 6.7 nM against HIV-2EHO, and 0.9 to 90 nM against laboratory-selected PI-resistant HIV-1 and clinical HIV-1 variants resistant to multiple FDA-approved PIs (HIVMDR). GRL-078, -079, -077, and -058 also effectively blocked the replication of HIV-1 variants highly resistant to darunavir (DRV) (HIVDRVrp51), with EC50s of 38, 62, 61, and 90 nM, respectively, while four FDA-approved PIs examined (amprenavir, atazanavir, lopinavir [LPV], and DRV) had virtually no activity (EC50s of >1,000 nM) against HIVDRVrp51. Structurally, GRL-078, -079, and -058 form strong hydrogen bond interactions between Tp-THF modified at C-5 and Asp29/Asp30/Gly48 of wild-type protease, while the P2′ Cp-Abt group forms strong hydrogen bonds with Asp30′. The Tp-THF and Cp-Abt moieties also have good nonpolar interactions with protease residues located in the flap region. For selection with LPV and DRV by use of a mixture of 11 HIVMDRstrains (HIV11MIX), HIV11MIXbecame highly resistant to LPV and DRV over 13 to 32 and 32 to 41 weeks, respectively. However, for selection with GRL-079 and GRL-058, HIV11MIXfailed to replicate at >0.08 μM and >0.2 μM, respectively. Thermal stability results supported the highly favorable anti-HIV-1 potency of GRL-079 as well as other PIs. The present data strongly suggest that the P2 Tp-THF group modified at C-5 and the P2′ Abt group contribute to the potent anti-HIV-1 profiles of the four PIs against HIV-1NL4-3and a wide spectrum of HIVMDRstrains.