PHI 346: A Novel Dual-Function Microbicide

描述（由申请人提供）：目前性传播的艾滋病毒/艾滋病大流行迫切需要一种新型杀微生物剂：一种既是杀精剂又是杀病毒剂的杀微生物剂。为了系统地开发一种阴道杀微生物避孕药，以防止I- V的性传播并提供生育控制，我们合成了一系列具有杀精活性的HIV-1逆转录酶（RT）的新型非核苷抑制剂（NNIs）。我们的基于结构的药物设计利用计算机对接程序对由9个RT-NNI晶体结构产生的NNI结合袋进行了合成，从而合成了一组杀精NNI。我们的先导化合物N-[2-（1-环己烯基）乙基]-N'-[2-（5-溴吡啶基）]-硫脲（PHI-346）是针对nni敏感、nni耐药和多重耐药的HIV-I株最有效、无细胞毒性、双功能的抗hiv药物。PHI-346的抗hiv活性比目前使用的基于洗涤剂的杀精剂nonoxyno]-9 （N-9）强700倍。ph -346的杀精活性是N-9的2倍，与N-9不同，它对女性生殖道上皮细胞的细胞毒性无关。临床前研究表明，在啮齿类动物和非啮齿类动物模型中，经阴道给药的PHI-346凝胶制剂缺乏炎症和毒性作用。我们推测，由于其广谱抗艾滋病毒活性，杀精效果，以及缺乏炎症和毒性作用，PHI-346可能是一种有用的双功能阴道/直肠杀微生物剂，用于通过性传播感染艾滋病毒/艾滋病的高风险妇女。进一步开发PHI-346作为一种双功能杀微生物剂，可能为预防多重耐药HIV-1性传播的新策略奠定基础，同时为妇女提供生育控制。本I期课题的目标是：(I)评估ph -346凝胶制剂在阴道hiv感染的性传播艾滋病小鼠模型中的体内抗hiv效果；（ii）评价ph -346凝胶制剂的体内避孕效果。在成功完成I期体内疗效研究后，ph -346的凝胶制剂将在II期进一步探索作为阴道双功能杀微生物剂。

DESCRIPTION (provided by applicant): The current pandemic of sexually transmitted HIV/AIDS has created an urgent need for a new type of microbicide: one that is both a spermicide and a virucide. In a systematic effort to develop a vaginal microbicidal contraceptive potentially capable of preventing the sexual transmission of I-]]V as well as providing fertility control, we have synthesized a series of novel nonnucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT) with spermicidal activity. Our structure-based drug design by use of a computer docking procedure for the NNI binding pocket generated from nine RT-NNI crystal structures led to the synthesis of a panel of spermicidal NNIs. Our lead compound, N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (PHI-346), was the most potent, non-cytotoxic, dual-function anti-HIV agent against NNI-sensitive, NNI-resistant, and multidrug-resistant strains of HIV-I. The anti-HIV activity of PHI-346 was 700-fold more potent than the currently used detergent-based virucidal spermicide, nonoxyno]-9 (N-9). The spermicidal activity of PHI-346 was 2-fold more potent than that of N-9 and unlike N-9, it was not associated with cytotoxicity to female genital tract epithelial cells. Preclinical studies of a PHI-346 gel formulation given intravaginally, lacked inflammatory and toxic effects in rodent and non-rodent animal models. We hypothesize that PHI-346, because of its broad-spectrum anti-HIV activity, spermicidal efficacy, and lack of inflammatory and toxic effects, may be useful as a dual-function vaginal/rectal microbicide for women who are at high risk of acquiring HIV/AIDS by sexual transmission. The further development of PHI-346 as a dual-function microbicide may provide the foundation for a new strategy to prevent the sexual transmission of multidrug-resistant HIV-1 while providing fertility control for women. The goal of this Phase I proposal is: (i) to evaluate the in vivo anti-HIV efficacy of PHI-346 gel formulation in the vaginal HIV-infected Hu-PBL-SCID mouse model of sexually transmitted AIDS; and (ii) to evaluate the in vivo contraceptive efficacy of PHI-346 gel formulation. Following successful completion of the Phase I in vivo efficacy studies, gel formulation of PHI-346 will be further explored as a vaginal dual-function microbicide in Phase II.