Design and Synthesis of New Generation anti-HIV agents Based on the X-ray analysis of Inhibitor-RT Complexes

基于抑制剂-RT 复合物 X 射线分析的新一代抗 HIV 药物的设计与合成

• 批准号: 09672159
• 负责人: TANAKA Hiromichi
• 金额: $ 1.92万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672159/
• 关键词: AIDS; Reverse Transcriptase; HIV-1; Allosteric Inhibitor; Resistant Virus; Amino Acid Mutation; NNRTI

Anti-HIV- I agent MKC-442 (generic name : emivirine), 6-benzyl- 1-ethoxymethyl-5-isopropyluracil, is now under Phase IIb clinical study in USA.Two single amino acid mutations, either Tyrl8lCys or LyslO3Asn, have been found in the Reverse Transcriptase (RT) of MKC-442-resistant HIV-1. The purpose of this study was to design and to synthesize MKC-442 analogues which show the activity even to theresistant strains.in the first finacial year, a series of compounds were design by computer-graphics based on the X-ray analysis data of the RT complexed with MKC-442. However, these compounds, having an omega-carbamoylalkyl substituent at the N1-position, showed uniformly lower activity than that of MKC-442, and were found not to be active against Tyrl8lCys.in the second year, it was found that TNK-6123, 6-cyclohexylthio-l-ethoxymethyi-5-isopropyluracil, shows significant activity against the Tyrl8lCys mutant. A 3000-fold reduced sensitivity of MKC-442 to this mutant was improved to be only 90-fold less sensitive in the case of TNK-6 123. The RT complexed with TNK-6 123 was analyzed again by X-ray crystallography, and the result is to be published shortly (submitted).

抗HIV-I药物MKC-442(通称：米韦林)，6-苄基-1-乙氧甲基-5-异丙基尿嘧啶，目前正在美国进行IIb期临床研究。在耐MKC-442的HIV-1的逆转录酶(RT)中发现了两个单一氨基酸突变，Tyr18lCys或LyslO3Asn。本研究的目的是设计和合成对耐药菌株仍有活性的MKC-442类似物。在第一个财政年度，根据与MKC-442络合的RT的X射线分析数据，利用计算机图形设计了一系列化合物。然而，这些化合物在N1位有一个omega-氨基甲酰基取代基，显示出比MKC-442更低的活性，并且对Tyr181Cys没有活性。第二年，发现TnK-6123，6-cyclohexylthio-l-ethoxymethyi-5-isopropyluracil，对Tyr181Cys突变体有显著的抑制活性。MKC-442对该突变体的敏感度降低了3000倍，而在TNK-6 123的情况下，敏感度仅降低了90倍。对与TNK-6 123形成络合物的RT再次进行了X射线结晶学分析，结果将于近期发表(提交)。

项目成果

H.Tanaka et al.: "Allosteric Inhibitors against HIV-1 RT : design and synthesis of MKC-442 analogues having ω-functionalized acyclic structure" Antiviral Chemistry and Chemotherapy. 9. 325-332 (1998)

H. Tanaka 等人：“针对 HIV-1 RT 的变构抑制剂：具有 ω-功能化无环结构的 MKC-442 类似物的设计和合成”抗病毒化学和化疗 9. 325-332 (1998)。