A conserved hydrogen-bonding network of P2 bis-tetrahydrofuran-containing HIV-1 protease inhibitors (PIs) with a protease active-site amino acid backbone aids in their activity against PI-resistant HIV.
A conserved hydrogen-bonding network of P2 bis-tetrahydrofuran-containing HIV-1 protease inhibitors (PIs) with a protease active-site amino acid backbone aids in their activity against PI-resistant HIV.
复制标题
含有 P2 双四氢呋喃的 HIV-1 蛋白酶抑制剂 (PI) 与蛋白酶活性位点氨基酸骨架的保守氢键网络有助于其对抗 PI 耐药的 HIV 的活性。
DOI：
10.1128/aac.00107-14
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发表时间：
2014
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：
Yedidi,RavikiranS;Garimella,Harisha;Aoki,Manabu;Aoki-Ogata,Hiromi;Desai,DarshanV;Chang,SimonB;Davis,DavidA;Fyvie,WSean;Kaufman,JoshuaD;Smith,DavidW;Das,Debananda;Wingfield,PaulT;Maeda,Kenji;Ghosh,ArunK;Mitsuya,Hiroaki
在本研究中，与利托那韦(RTV；EC50，>；1.0μM)和替普拉韦(TPV；EC50，0.364μM)相比，新型非肽类人类免疫缺陷病毒1型蛋白酶抑制剂GRL008和达鲁那韦(Darunavir)对多重耐药的HIV-1临床分离株(HIVA02)具有强大的抗病毒活性(50%有效浓度[EC50]，分别为0.029和0.002μM)。此外，GRL008对在20代DRV存在下选择的HIV-1变种(HIVDRVRP20)显示出强大的抗病毒活性，其EC50(0.097μM)是其对野生型HIV-1NL4-3(HIVWT)的相应EC50(0.038μM)的2.6倍。根据X射线晶体分析，GRL008和DRV都与HIVA02酶(PRA02)的保守活性中心氨基酸G27、D29、D30和D30‘以及野生型PR在各自的晶体结构中显示出较强的氢键(H键)，而TPV由于没有极性基团而与G27和D30’缺乏氢键。RTV的P2‘-噻唑基部分在PrA02-RTV复合体的晶体结构中显示出两种构象，其中一种在PrA02的S2’结合口袋中失去了接触，支持RTV的抗病毒活性(EC501μM)。因此，含有P2-bis-THF的GRL008与G27、D29、D30和D30‘的骨架组成的保守的氢键网络很可能是其持续具有较强的抗HIVWT、HIVA02和HIVDRVRP20活性的原因。
In the present study, GRL008, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), and darunavir (DRV), both of which contain a P2-bis-tetrahydrofuranyl urethane (bis-THF) moiety, were found to exert potent antiviral activity (50% effective concentrations [EC50s], 0.029 and 0.002 μM, respectively) against a multidrug-resistant clinical isolate of HIV-1 (HIVA02) compared to ritonavir (RTV; EC50, >1.0 μM) and tipranavir (TPV; EC50, 0.364 μM). Additionally, GRL008 showed potent antiviral activity against an HIV-1 variant selected in the presence of DRV over 20 passages (HIVDRVRP20), with a 2.6-fold increase in its EC50(0.097 μM) compared to its corresponding EC50(0.038 μM) against wild-type HIV-1NL4-3(HIVWT). Based on X-ray crystallographic analysis, both GRL008 and DRV showed strong hydrogen bonds (H-bonds) with the backbone-amide nitrogen/carbonyl oxygen atoms of conserved active-site amino acids G27, D29, D30, and D30′ of HIVA02protease (PRA02) and wild-type PR in their corresponding crystal structures, while TPV lacked H-bonds with G27 and D30′ due to an absence of polar groups. The P2′ thiazolyl moiety of RTV showed two conformations in the crystal structure of the PRA02-RTV complex, one of which showed loss of contacts in the S2′ binding pocket of PRA02, supporting RTV's compromised antiviral activity (EC50, >1 μM). Thus, the conserved H-bonding network of P2-bis-THF-containing GRL008 with the backbone of G27, D29, D30, and D30′ most likely contributes to its persistently greater antiviral activity against HIVWT, HIVA02, and HIVDRVRP20.