Mechanism of resistance to S138A substituted enfuvirtide and its application to peptide design.
Mechanism of resistance to S138A substituted enfuvirtide and its application to peptide design.
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DOI：
10.1016/j.biocel.2013.01.015
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Kodama EN
中科院分区：
文献类型：
--
作者：
Izumi K;Kawaji K;Miyamoto F;Shimane K;Shimura K;Sakagami Y;Hattori T;Watanabe K;Oishi S;Fujii N;Matsuoka M;Kaku M;Sarafianos SG;Kodama EN
T-20（恩夫韦地）耐药性是由gp 41的N末端七肽重复序列（N-HR）的推定结合位点处的N43 D初级耐药性突变以及gp 41的C末端HR（C-HR）处的S138 A二级突变引起的。我们已经发现，将T-20修饰为包含S138 A（T-20 S138 A）允许其通过一种机制有效地阻断野生型和T20抗性病毒，该机制涉及T-20 S138 A与含有N43 D初级突变的N-HR的结合改善。为了确定HIV-1如何反过来逃避T-20 S138 A，我们使用剂量递增方法从野生型（HIV-1 WT）或T-20抗性（HIV-1 N43 D/S138 A）病毒开始选择T-20 S138 A抗性HIV-1。我们发现，当以WT背景开始时，gp 41的N-HR中出现I37 N和L44 M，C-HR中出现N126 K;而当以HIV-1 N43 D/S138 A开始时，N-HR中出现L33 S和I69 L，C-HR中出现E137 K。提示T-20 S138 A通过与T-20相似的机制抑制HIV-1复制。此外，E137 K增强了病毒复制动力学，并恢复了与含有N43 D的N-HR的结合亲和力，表明其作为次级补偿突变。因此，我们将E137 K引入T-20 S138 A（T-20 E137 K/S138 A），并发现T-20 E137 K/S138 A中度抑制T-20 S138 A抗性HIV-1的复制。T-20 E137 K/S138 A保留了对HIV-1的活性，而没有L33 S，这似乎是T-20衍生物的关键突变。我们的数据表明，二次突变可以始终用于设计肽抑制剂，阻断HIV的复制耐融合抑制剂。
T-20 (enfuvirtide) resistance is caused by the N43D primary resistance mutation at its presumed binding site at the N-terminal heptad repeat (N-HR) of gp41, accompanied by the S138A secondary mutation at the C-terminal HR of gp41 (C-HR). We have discovered that modifying T-20 to include S138A (T-20S138A) allows it to efficiently block wild-type and T20-resistant viruses, by a mechanism that involves improved binding of T-20S138A to the N-HR that contains the N43D primary mutation. To determine how HIV-1 in turn escapes T-20S138A we used a dose escalation method to select T-20S138A-resistant HIV-1 starting with either wild-type (HIV-1WT) or T-20-resistant (HIV-1N43D/S138A) virus. We found that when starting with WT background, I37N and L44M emerged in the N-HR of gp41, and N126K in the C-HR. However, when starting with HIV-1N43D/S138A, L33S and I69L emerged in N-HR, and E137K in C-HR. T-20S138A-resistant recombinant HIV-1 showed cross-resistance to other T-20 derivatives, but not to C34 derivatives, suggesting that T-20S138A suppressed HIV-1 replication by a similar mechanism to T-20. Furthermore, E137K enhanced viral replication kinetics and restored binding affinity with N-HR containing N43D, indicating that it acts as a secondary, compensatory mutation. We therefore introduced E137K into T-20S138A (T-20E137K/S138A) and revealed that T-20E137K/S138A moderately suppressed replication of T-20S138A-resistant HIV-1. T-20E137K/S138A retained activity to HIV-1 without L33S, which seems to be a key mutation for T-20 derivatives. Our data demonstrate that secondary mutations can be consistently used for the design of peptide inhibitors that block replication of HIV resistant to fusion inhibitors.
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影响因子：
7.3
作者：
Debnath, AK;Radigan, L;Jiang, SB
通讯作者：
Jiang, SB
影响因子：
2.9
作者：
Bai, Xuefang;Wilson, Karen L.;Dwyer, John J.
通讯作者：
Dwyer, John J.
影响因子：
5.6
作者：
Cardoso, Rosa M. F.;Brunel, Florence M.;Wilson, Ian A.
通讯作者：
Wilson, Ian A.
影响因子：
5.4
作者：
Eggink, Dirk;Bontjer, Ilja;Sanders, Rogier W.
通讯作者：
Sanders, Rogier W.
DOI：
10.1073/pnas.95.26.15613
发表时间：
1998-12-22
影响因子：
11.1
作者：
Chan, DC;Chutkowski, CT;Kim, PS
通讯作者：
Kim, PS