Discovery of 2,5-dimethoxy-substituted 5-bromopyridyl thiourea (PHI-236) as a potent broad-spectrum anti-human immunodeficiency virus microbicide.
Discovery of 2,5-dimethoxy-substituted 5-bromopyridyl thiourea (PHI-236) as a potent broad-spectrum anti-human immunodeficiency virus microbicide.
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发现 2,5-二甲氧基取代的 5-溴吡啶基硫脲 (PHI-236) 作为一种有效的广谱抗人类免疫缺陷病毒杀微生物剂。
DOI：
10.1093/molehr/gah236
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发表时间：
2005
影响因子：
4
通讯作者：
Uckun,FatihM
中科院分区：
文献类型：
--
作者：
D'Cruz,OsmondJ;Uckun,FatihM
人类免疫缺陷病毒-1（HIV-1）异性性传播的风险增加，促使人们寻找安全有效的女性控制的阴道杀微生物剂。由于内源性逆转录参与增强HIV-1的性传播，潜在的杀微生物剂应具有最佳抑制HIV-1的野生型和耐药突变株的固有能力。（二、5-二甲氧基苯乙基）]-N ′-[2-（5-溴吡啶基）]-硫脲（PHI-236）是一种合理设计的HIV-1逆转录酶（NNRTI）的非核苷抑制剂，由临床观察到的NNRTI耐药突变导致的形状和残基特征。PHI-236对HIV-1 RT显示出高结合亲和力（LudiKi = 0.07 µ M），对野生型（IC50 =<0.001 µ M）以及携带与NRTI和NNRTI耐药相关的多种RT基因突变的主要临床分离株（IC50 = 0.009 - 0.04 µ M）具有稳健的抗HIV活性。PHI-236对人阴道和宫颈上皮细胞显示出高选择性指数，并且不影响人精子功能。在HIV/获得性免疫缺陷综合征（AIDS）的人源化严重联合免疫缺陷小鼠模型中，用PHI-236预处理HIV-1（BaL）感染的人单核细胞和精液可预防经阴道途径的全身感染。PHI-236作为一种非杀精子的杀微生物剂以及预防性抗病毒剂在辅助生殖技术程序之前抑制精液中的无细胞和细胞相关的HIV-1具有特殊的临床用途。
The increased risk of heterosexual transmission of human immunodeficiency virus-1 (HIV-1) has prompted the search for safe and effective female-controlled vaginal microbicides. Because endogenous reverse transcription is implicated in augmenting the sexual transmission of HIV-1, potential microbicides should have the inherent ability to optimally inhibit both wild-type and drug-resistant mutant strains of HIV-1.N-[2-(2,5-dimethoxyphenylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (PHI-236) is a rationally designed non-nucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI) that was deduced from changes in binding pocket size, shape and residue character that result from clinically observed NNRTI resistance mutations. PHI-236 displayed high-binding affinity (LudiKi= 0.07 µM) for HIV-1 RT and robust anti-HIV activity against the wild type (IC50= <0.001 µM) as well as primary clinical isolates (IC50= 0.009–0.04 µM) carrying multiple RT gene mutations associated with NRTI and NNRTI resistance. PHI-236 displayed high-selectivity index against human vaginal and cervical epithelial cells and did not affect human sperm functions. In the humanized severe combined immunodeficient mouse model for HIV/acquired immune deficiency syndrome (AIDS), pretreatment of HIV-1 (BaL)-infected human monocytes and semen with PHI-236 prevented the systemic infection via the vaginal route. PHI-236 has particular clinical utility as a non-spermicidal microbicide as well as a prophylactic antiviral agent to inactivate cell-free and cell-associated HIV-1 in semen before assisted reproductive technology procedures.