The higher barrier of darunavir and tipranavir resistance for HIV-1 protease.
The higher barrier of darunavir and tipranavir resistance for HIV-1 protease.
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DOI：
10.1016/j.bbrc.2011.08.045
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发表时间：
2011-09-09
影响因子：
3.1
通讯作者：
Kovari, Ladislau C.
中科院分区：
文献类型：
--
作者：
Wang, Yong;Liu, Zhigang;Brunzelle, Joseph S.;Kovari, Iulia A.;Dewdney, Tamaria G.;Reiter, Samuel J.;Kovari, Ladislau C.
达芦那韦和替拉那韦是两种对多药耐药（MDR）HIV-1蛋白酶变体有活性的抑制剂。本研究对一种MDR HIV-1蛋白酶变异株MDR 769 82 T进行了体外抑制试验，MDR 769 82 T含有46 L/54 V/82 T/84 V/90 M耐药突变。进行了晶体学和酶学研究，以检查耐药机制和效价的相对维持。主要发现如下：（i）MDR蛋白酶表现出对美国食品和药物管理局（FDA）批准的所有九种HIV-1蛋白酶抑制剂的敏感性降低，其中地瑞那韦和替拉那韦是最有效的;（ii）蛋白酶上的苏氨酸82突变通过改变结合口袋的疏水性大大增强了耐药性;（iii）地瑞那韦或替拉那韦结合促进MDR蛋白酶的完全开放的瓣的闭合;和（iv）通过稳定化所述蛋白酶-蛋白酶复合物中的瓣可以保持替拉那韦的剩余效力，而地瑞那韦通过保持蛋白质主链与柔性P2基团的氢键来保持其效力。这些结果可以为药物设计策略提供新的见解，以克服HIV-1蛋白酶变体的多药耐药性。
Darunavir and tipranavir are two inhibitors that are active against multi-drug resistant (MDR) HIV-1 protease variants. In this study, the in vitro inhibitory efficacy was tested against a MDR HIV-1 protease variant, MDR 769 82T, containing the drug resistance mutations of 46L/54V/82T/84V/90M. Crystallographic and enzymatic studies were performed to examine the mechanism of resistance and the relative maintenance of potency. The key findings are as follows: (i) The MDR protease exhibits decreased susceptibility to all nine HIV-1 protease inhibitors approved by the U.S. Food and Drug Administration (FDA), among which darunavir and tipranavir are the most potent; (ii) the threonine 82 mutation on the protease greatly enhances drug resistance by altering the hydrophobicity of the binding pocket; (iii) darunavir or tipranavir binding facilitates closure of the wide-open flaps of the MDR protease; and (iv) the remaining potency of tipranavir may be preserved by stabilizing the flaps in the inhibitor-protease complex while darunavir maintains its potency by preserving protein main chain hydrogen bonds with the flexible P2 group. These results could provide new insights into drug design strategies to overcome multi-drug resistance of HIV-1 protease variants.
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影响因子：
3.4
作者：
Tenore, S.B.;Ferreira, P.R.A.
通讯作者：
Ferreira, P.R.A.
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：
1.6
作者：
Vickrey, JF;Logsdon, BC;Kovari, LC
通讯作者：
Kovari, LC
DOI：
10.1093/protein/8.2.127
发表时间：
1995-02-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
WALLACE, AC;LASKOWSKI, RA;THORNTON, JM
通讯作者：
THORNTON, JM
影响因子：
3.5
作者：
Ghosh, Arun K.;Dawson, Zachary L.;Mitsuya, Hiroaki
通讯作者：
Mitsuya, Hiroaki