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首页> 外文期刊>Antiviral chemistry & chemotherapy >Mechanism of interaction of novel indolylarylsulfone derivatives with K103N andY181I mutant HIV-1 reverse transcriptase in complex with its substrates.
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Mechanism of interaction of novel indolylarylsulfone derivatives with K103N andY181I mutant HIV-1 reverse transcriptase in complex with its substrates.

机译：用K103N和y181I突变体HIV-1逆转录酶与其基质相互作用的新吲哚砜衍生物的机制。

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BACKGROUND: Novel indolylarylsulfones (IASs), designed through rationalstructure-based molecular modelling and docking approaches, have been recentlycharacterized as effective inhibitors of the wild-type and drug-resistant mutant HIV-1 reverse transcriptase (RT).METHODS: Here, we studied the interaction of selected halo- and nitro-substitutedIAS derivatives, with the RT enzyme carrying the single resistance mutationsK103N and Y181I through steady-state kinetic experiments.RESULTS: The studied compounds exhibited high selectivity to the mutant RT incomplex with its substrates, behaving as uncompetitive inhibitors. The presenceof the K103N mutation, and to a lesser extent the Y181I, stabilized the druginteractions with the viral RT, when both its substrates were bound.CONCLUSIONS: The characterization of these mutation-specific effects on inhibitorbinding might be relevant to the design of more effective new generationnon-nucleoside reverse transcriptase inhibitors, with better resilience towardsdrug resistant mutants.PMID: 22095519 [PubMed - in process]4. Antivir Chem Chemother. 2011 Nov 17;22(3):95-105.HIV-1 integrase inhibitors: a review of their chemical development.Ingale KB, Bhatia MS.Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy,Kolhapur, India. kundan.i@rediffmail.comHighly active antiretroviral therapy (HAART) significantly decreases plasma viralload, increases CD4+ T-cell counts in HIV-1-infected patients and has reducedprogression to AIDS in developed countries. However, adverse side effects, andemergence of drug resistance, mean there is still a demand for new anti-HIVagents. The HIV integrase (IN) is a target that has been the focus of rationaldrug design over the past decade. In 2007, raltegravir was the first IN inhibitorapproved by the US Food and Drug Administration for antiretroviral combinationtherapy, while another IN inhibitor, elvitegravir, is currently in Phase IIIclinical trials. This article reviews the development and resistance profiling ofsmall molecule HIV-1 IN inhibitors.
机译：背景：通过基于理性结构的分子建模和对接方法设计的新型吲哚甲醛（IASS）已被最终进行特征，作为野生型和耐药突变体HIV-1逆转录酶（RT）的有效抑制剂。方法：在这里，我们研究过选择卤代和硝基 - 替代衍生物的相互作用，具有稳态动力学实验的RT酶与携带单抗性突变k103n和y181i携带的RT酶。结果：所研究的化合物对突变体RT incomplex与其基材具有高选择性，表现为缺乏竞争物抑制剂。 K103N突变的存在，以及在较小程度上，Y181i的程度与病毒RT稳定，当其均合并时，稳定药物互补活动。链接性：这些突变特异性对抑制作用的表征可能与更有效的设计相关新一代核苷逆转录酶抑制剂，具有更好的抗性抗性突变体.PMID：22095519 [PUBMED-IN工艺] 4。 AntiVir Chem Chemother。 2011年11月17日; 22（3）：95-105.Hiv-1整合酶抑制剂：对其化学发育的综述。标志KB，Bhatia MS.Department的药物化学，Bharati Vidyapeeth药房，Kolhapur，印度。 kundan.i@rediffmail.com高活跃的抗逆转录病毒治疗（HAART）显着降低了血浆病毒，增加了HIV-1感染患者的CD4 + T细胞计数，并在发达国家的艾滋病方面减少了。然而，不良副作用，抗药物的恶毒症，意味着对新的抗病症仍有需求。艾滋病毒整合酶（IN）是过去十年的理性设计焦点的目标。 2007年，Raltegravir是美国食品和药物管理局批准的抑制作用，而抗逆转录病毒尿症的抑制作用，而另一个在抑制剂elvitegravir，目前处于IIICLI外试验。本文综述了抑制剂中的抑制剂中的Small分子HIV-1的开发和阻力分析。

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