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Structure based design of potent inhibitors against multidrug-resistant HIV-1 protease variants.

机译：基于结构的抗多药HIV-1蛋白酶变体有效抑制剂的设计。

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摘要

The current study is focused on designing potent inhibitors against multidrug-resistant strains of HIV-1 protease, a critical enzyme required for the viral replication, maturation and infectivity. Due to the error prone rapid replication of the virus, mutations are randomly incorporated into the viral proteins. Accumulation of mutations leads to changes in the secondary structure of the viral proteins that may hinder the viral replication as well as cause drug resistance. HIV-1 protease is a small homodimeric aspartic protease which cleaves the long viral polyproteins into mature individual proteins that are packed into a functional infective virion. Due to its critical role, the viral protease is a very important drug target. Currently there are ten FDA approved inhibitors against HIV-1 protease that are used as a part of the combination therapy. Due to the accumulation of various mutations, drug resistant variants of HIV-1 protease are selected during the therapy. Some of these clinical isolates are multidrug-resistant (MDR) variants.;One such MDRHIV-1 protease was chosen as the drug target in the current study. Structure-function studies of an ensemble of MDR protease variants revealed that there is a conserved trend in active site expansion with wide-open flaps. Some mutants even showed proline switch (reported for the first time) that might even worsen the drug resistance problem. Crystal structures of these mutants show loss of contacts mainly due to lack of induced fit conformational changes in the protease upon ligand binding. FRET based enzyme assays showed that MDR769 HIV-1 protease is ten fold resistant against the current drugs.;The expanded active site cavity of the MDR protease was scanned using a library of heptapeptides that mimic the CA/p2 cleavage site. Among the library of nine peptides, one was identified as a lead peptide with a subnanomolar inhibition capability. This peptide was further studied and was used as a template to design potent compounds that can be used as inhibitors against such ensemble of MDR protease variants. These compounds are to be synthesized and tested in future. The pharmacological properties of these drugs are to be further studied in order to use them as a part of combination therapy.
机译：目前的研究集中在设计针对HIV-1蛋白酶多重耐药菌株的有效抑制剂，HIV-1蛋白酶是病毒复制，成熟和感染力所需的关键酶。由于容易出错的病毒快速复制，突变被随机掺入病毒蛋白中。突变的积累导致病毒蛋白质二级结构的改变，这可能会阻碍病毒的复制并引起耐药性。 HIV-1蛋白酶是一种小的同型二聚天冬氨酸蛋白酶，可将长的病毒多蛋白切割成成熟的单个蛋白，这些蛋白被包装成功能性感染性病毒体。由于其关键作用，病毒蛋白酶是非常重要的药物靶标。目前，有十种FDA批准的HIV-1蛋白酶抑制剂被用作联合疗法的一部分。由于各种突变的积累，在治疗期间选择了HIV-1蛋白酶的抗药性变体。这些临床分离物中的一些是耐多药（MDR）变体。在当前研究中，一种这样的MDRHIV-1蛋白酶被选为药物靶标。 MDR蛋白酶变体集合的结构功能研究表明，在活动位点扩展的情况下，皮瓣全开存在保守的趋势。一些突变体甚至显示出脯氨酸转换（首次报道），这甚至可能使耐药性问题恶化。这些突变体的晶体结构显示失去接触，这主要是由于配体结合后蛋白酶中缺乏诱导的适合构象变化。基于FRET的酶分析表明，MDR769 HIV-1蛋白酶对当前药物具有十倍的抗药性;使用模拟CA / p2切割位点的七肽库扫描了MDR蛋白酶扩展的活性位点腔。在九种肽的文库中，一种被鉴定为具有亚纳摩尔抑制能力的前导肽。对该肽进行了进一步的研究，并将其用作模板来设计有效的化合物，这些化合物可用作针对这种MDR蛋白酶变体集合的抑制剂。这些化合物将在未来进行合成和测试。这些药物的药理特性有待进一步研究，以将其用作联合治疗的一部分。

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  • 作者

    Yedidi, Ravikiran S.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Chemistry Biochemistry.;Health Sciences Pharmacy.;Biophysics Medical.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 124 p.
  • 总页数 124
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;药剂学;生物物理学;
  • 关键词

  • 入库时间 2022-08-17 11:38:26

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