PHI 346: A Novel Dual-Function Microbicide

描述（由申请人提供）： 目前通过性传播的艾滋病毒/艾滋病的流行迫切需要一种新型的杀微生物剂：既杀精子又杀病毒的杀微生物剂。在一项系统的努力，以开发一种阴道杀微生物避孕药，可能能够防止性传播的I-]]V以及提供生育控制，我们已经合成了一系列新的非核苷抑制剂（NNI）的HIV-1逆转录酶（RT）的杀精活性。我们的基于结构的药物设计，通过使用计算机对接程序的NNI结合口袋产生的九个RT-NNI晶体结构，导致了一组杀精子NNI的合成。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抗性和多药抗性HIV-I菌株的最有效、无细胞毒性、双功能抗HIV剂。PHI-346的抗HIV活性比目前使用的基于去污剂的杀病毒杀精剂壬苯氧基[nonoxyno]-9（N-9）强700倍。PHI-346的杀精子活性是N-9的2倍，并且与N-9不同，其与对女性生殖道上皮细胞的细胞毒性无关。阴道内给予的PHI-346凝胶制剂的临床前研究在啮齿动物和非啮齿动物模型中没有炎症和毒性作用。我们假设，由于其广谱抗HIV活性，杀精功效，以及缺乏炎症和毒性作用，PHI-346可能是有用的双重功能的阴道/直肠杀微生物剂的妇女谁是在获得艾滋病毒/艾滋病的高风险性传播。进一步开发PHI-346作为双功能杀微生物剂可能为预防耐多药HIV-1性传播的新战略奠定基础，同时为妇女提供生育控制。该I期提案的目的是：（i）评价PHI-346凝胶制剂在性传播AIDS的阴道HIV感染的Hu-PBL-SCID小鼠模型中的体内抗HIV功效;和（ii）评价PHI-346凝胶制剂的体内避孕功效。在成功完成I期体内功效研究之后，将在II期中进一步探索PHI-346的凝胶制剂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.