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

抗HIV-I药物MKC-442（通用名emivirine），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。本研究的目的是设计和合成具有抗肿瘤活性的MKC-442类似物。第一年，根据RT与MKC-442复合物的X-射线分析数据，利用计算机图形学设计了一系列化合物。strains.in然而，在N1-位具有ω-氨基甲酰基烷基取代基的这些化合物显示出一致低于MKC-442的活性，并且发现对Tyrl8lCys.in没有活性。第二年，发现TNK-6123（6-环己基硫代-1-乙氧基甲基-5-异丙基尿嘧啶）显示出对Tyr 181 Cys突变体的显著活性。MKC-442对该突变体的敏感性降低了3000倍，在TNK-6 123的情况下，其敏感性仅降低了90倍。通过X射线晶体学再次分析了与TNK-6 123复合的RT，结果将很快发表（已提交）。

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).