PHI 346: A Novel Dual-Function Microbicide

PHI 346：一种新型双功能杀菌剂

基本信息

批准号：
6590093
负责人：
OSMOND J D'CRUZ
金额：
$ 10万
依托单位：
PARADIGM PHARMACEUTICALS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-01-01 至 2003-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6590093
关键词：
AIDS education /prevention SCID mouse antiAIDS agent antiviral agents chemical synthesis contraceptives drug design /synthesis /production human tissue reverse transcriptase inhibitors semen sexually transmitted diseases spermicide vagina

项目摘要

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.

描述（由申请人提供）：当前性传播艾滋病毒/艾滋病的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菌避孕药，该避孕药可能能够预防 I-]]V 的性传播并提供生育控制，我们合成了一系列新型 HIV-1 逆转录酶 (RT) 非核苷抑制剂 (NNI) ）具有杀精活性。我们基于结构的药物设计通过使用计算机对接程序对九个 RT-NNI 晶体结构生成的 NNI 结合袋进行设计，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) 是最有效的、无细胞毒性的双功能抗-针对 NNI 敏感、NNI 耐药和多重耐药 HIV-I 菌株的 HIV 药剂。 PHI-346 的抗 HIV 活性比目前使用的基于清洁剂的杀病毒剂 nonoxyno]-9 (N-9) 强 700 倍。 PHI-346 的杀精活性比 N-9 强 2 倍，并且与 N-9 不同，它与女性生殖道上皮细胞的细胞毒性无关。阴道内给药的 PHI-346 凝胶制剂的临床前研究在啮齿类和非啮齿类动物模型中缺乏炎症和毒性作用。我们假设 PHI-346 由于其广谱抗 HIV 活性、杀精功效以及无炎症和毒性作用，可能可作为双功能阴道/直肠杀菌剂，用于感染艾滋病毒高风险的女性。艾滋病毒/艾滋病通过性传播。 PHI-346 作为双功能杀菌剂的进一步开发可能为防止多重耐药 HIV-1 性传播同时为女性提供生育控制的新策略奠定基础。该第一阶段提案的目标是：(i) 评估 PHI-346 凝胶制剂在阴道感染 HIV 的性传播艾滋病 Hu-PBL-SCID 小鼠模型中的体内抗 HIV 功效； (ii) 评估 PHI-346 凝胶制剂的体内避孕功效。在成功完成 I 期体内功效研究后，PHI-346 的凝胶制剂将在 II 期进一步探索作为阴道双功能杀菌剂。