PHI-443: Novel Non-Spermicidal Anti-HIV Microbicide

PHI-443：新型非杀精抗 HIV 杀菌剂

• 批准号: 6695246
• 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
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-28 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6695246
• 关键词: AIDS education /prevention; SCID mouse; antiAIDS agent; antiviral agents; clinical research; communicable disease control; communicable disease transmission; drug resistance; drug screening /evaluation; emulsions; gel; human immunodeficiency virus 1; human subject; laboratory rabbit; pharmacokinetics; sexually transmitted diseases; spermicide; vagina

DESCRIPTION (provided by applicant): The emergence of AIDS as a disease spread through sexual intercourse has prompted the search for new, effective, safe, and female-controlled vaginal microbicides for curbing mucosal viral transmission. Microbicides would provide protection by inactivating viruses or preventing viruses from replicating either in semen or the infected host cells that line the vaginal wall. Through an integrated effort involving synthesis, docking studies, and biological evaluation, we identified a thiophene thiourea non-nucleoside inhibitor (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea [PHI-443]) with unprecedented potency against genotypic and phenotypic drug-resistant HIV-1 strains. PHI-443 had no effect on human sperm functions even at a concentration 30,000-times higher than it in vitro anti-HIV activity. PHI-443 showed favorable pharmacokinetics and did not cause acute or subacute toxicity in mice. The discovery of PHI-443 as a non-spermicidal, non-toxic, broad-spectrum anti-HIV agent represents a significant step forward in the development of a microbicide for curbing heterosexual HIV transmission. Non-spermicidal anti-HIV agents that are highly active against genotypic and phenotypic drug-resistant primary clinical HIV-1 isolates will be a tremendous advantage for the development of a broad-spectrum anti-HIV microbicide since a high percentage of newly infected individuals in the US harbor drug-resistant mutants. As a non-spermicidal prophylactic microbicide, PHI-443 will be useful for (i) sexually active women to allow pregnancy while protecting both mother and child from HIV and; (ii) as a prophylactic antiviral agent, especially for HIV-1 serodiscordant couples before assisted reproductive technology procedures are undertaken. The goals of this Phase I proposal are: (i) to examine the microbicidal activity of PHI-443 containing gel-microemulsion in vaginal HIV-1 infected Hu-PBL-SCID mouse model of sexually transmitted AIDS; and (ii) to perform pilot studies aimed at the evaluation of the tissue compatibility, safety, and pharmacokinetic analysis of PHI-443 gel formulation in the rabbit model. Specific Aims 1 and 2 may provide the foundation for the clinical development of PHI-443 in Phase II studies as a safe, effective broad-spectrum anti-HIV microbicide without conception-inhibiting functions.

描述（由申请人提供）：艾滋病作为一种通过性交传播的疾病的出现促使人们寻找新的、有效的、安全的、女性控制的阴道杀微生物剂来抑制粘膜病毒传播。杀微生物剂可以通过灭活病毒或防止病毒在精液或阴道壁受感染的宿主细胞中复制来提供保护。通过合成、对接研究和生物学评价等综合努力，我们鉴定了一种噻吩硫脲非核苷抑制剂（N'-[2-(2-噻吩)乙基]-N'-[2-(5-溴吡啶基)]）硫脲 [PHI-443]）对基因型和表型耐药 HIV-1 菌株具有前所未有的效力。即使浓度比其体外抗 HIV 活性高 30,000 倍，PHI-443 也不会对人类精子功能产生影响。 PHI-443 显示出良好的药代动力学，并且不会在小鼠中引起急性或亚急性毒性。 PHI-443 作为一种非杀精、无毒、广谱抗 HIV 药物的发现代表了开发用于遏制异性 HIV 传播的杀微生物剂的重要一步。非杀精抗 HIV 药物对基因型和表型耐药的初级临床 HIV-1 分离株具有高度活性，这对于开发广谱抗 HIV 杀微生物剂将具有巨大优势，因为新感染者中新感染者的比例很高。美国存在耐药突变体。作为一种非杀精预防性杀菌剂，PHI-443 将有助于 (i) 性活跃的女性怀孕，同时保护母亲和孩子免受艾滋病毒感染； (ii) 作为预防性抗病毒药物，尤其是在进行辅助生殖技术程序之前，对于 HIV-1 血清不一致的夫妇而言。该第一阶段提案的目标是： (i) 在阴道 HIV-1 感染的性传播艾滋病 Hu-PBL-SCID 小鼠模型中检查含有 PHI-443 的凝胶微乳剂的杀菌活性； (ii) 进行初步研究，旨在评估 PHI-443 凝胶制剂在兔模型中的组织相容性、安全性和药代动力学分析。具体目标 1 和 2 可能为 PHI-443 作为安全、有效的广谱抗 HIV 杀菌剂（不具有受孕抑制功能）的 II 期研究临床开发奠定基础。