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

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、女性控制的阴道杀菌剂来抑制粘膜病毒传播。杀微生物剂可以通过灭活病毒或阻止病毒在精液或阴道壁上的受感染宿主细胞中复制来提供保护。通过综合合成、对接研究和生物学评价，我们发现了一种噻吩-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的HIV-1菌株具有前所未有的效力。即使ph -443浓度比体外抗hiv活性高3万倍，对人类精子功能也没有影响。ph -443在小鼠体内表现出良好的药代动力学，不引起急性或亚急性毒性。PHI-443作为一种非杀精、无毒、广谱的抗艾滋病毒药物的发现，在抑制异性恋艾滋病毒传播的杀微生物剂的开发中迈出了重要的一步。非杀精抗hiv药物对基因型和表型耐药的原发性临床HIV-1分离株具有高度活性，这将是开发广谱抗hiv杀微生物剂的巨大优势，因为在美国有很高比例的新感染个体携带耐药突变体。作为一种非杀精性的预防性杀菌剂，PHI-443将有助于(i)性活跃的妇女怀孕，同时保护母亲和儿童免受艾滋病毒感染；（ii）作为预防性抗病毒药物，特别是在进行辅助生殖技术程序之前对HIV-1血清不一致的夫妇。本I期计划的目标是：(I)在阴道HIV-1感染的性传播艾滋病的Hu-PBL-SCID小鼠模型中检测含有ph -443凝胶微乳的杀微生物活性；（ii）进行初步研究，旨在评估ph -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pi -443在II期研究中作为一种安全、有效的广谱抗hiv杀微生物剂的临床开发提供基础。

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.