Mechanism of drug resistance due to N88S in CRF01_AE HIV-1 protease, analyzed by molecular dynamics simulations
Mechanism of drug resistance due to N88S in CRF01_AE HIV-1 protease, analyzed by molecular dynamics simulations
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DOI：
10.1021/jm061158i
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发表时间：
2007-04-19
影响因子：
7.3
通讯作者：
Sugiura, Wataru
中科院分区：
文献类型：
--
作者：
Ode, Hirotaka;Matsuyama, Shou;Sugiura, Wataru
奈非那韦(Nelfinavir，NFV)是目前可用的HIV-1蛋白水解酶(PR)抑制剂。NFV治疗失败的患者主要携带HIV-1 PR的D30N突变株，如果他们感染了B亚型病毒。相比之下，HIV-1 PR的N88S突变主要出现在NFV治疗失败和携带CRF01_AE病毒的患者中。D30N和N88S都具有对NFV的抗性。然而，目前还不清楚为什么非活性位点突变N88S会对NFV产生抗性。在这项研究中，我们通过计算模拟来研究抗性机制。模拟结果表明，尽管存在非活性位点突变，但N88S通过减少PR和NFV之间的相互作用而导致NFV耐药。我们还研究了为什么B亚型和CRF01_AE型HIV-1的D30N和N88S的出苗率不同。模拟结果表明，CRF01_AE PR基因的多态性与耐药突变株的出现率有关。
Nelfinavir (NFV) is a currently available HIV-1 protease (PR) inhibitor. Patients in whom NFV treatment has failed predominantly carry D30N mutants of HIV-1 PRs if they have been infected with the subtype B virus. In contrast, N88S mutants of HIV-1 PRs predominantly emerge in patients in whom NFV treatment has failed and who carry the CRF01_AE virus. Both D30N and N88S confer resistance against NFV. However, it remains unclear why the nonactive site mutation N88S confers resistance against NFV. In this study, we examined the resistance mechanism through computational simulations. The simulations suggested that despite the nonactive site mutation, N88S causes NFV resistance by reducing interactions between PR and NFV. We also investigated why the emergence rates of D30N and N88S differ between subtype B and CRF01_AE HIV-1. The simulations suggested that polymorphisms of CRF01_AE PR are involved in the emergence rate of the drug-resistant mutants.