Stampidine: A Novel Broad-Spectrum 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、女性控制的阴道杀微生物剂，以抑制粘膜病毒传播。目前正在研究的杀微生物剂主要是为了防止怀孕以及防止性传播疾病。提供非杀精子的杀微生物剂对于以下两方面同样重要：（一）性活跃的妇女，使其能够怀孕，同时保护母亲和子女免受艾滋病毒感染;（二）作为预防性抗病毒剂，特别是在进行辅助生殖技术程序之前，对艾滋病毒1型血清不一致的夫妇。为了系统地鉴定一种广谱抗HIV杀微生物剂，该杀微生物剂可能能够预防HIV的性传播而不影响生育力，我们合成了一系列司他夫定的磷酸苯酯衍生物（STV/d4 T），并鉴定了司他夫定-5 '-（对溴苯基甲氧丙氨酰磷酸）[Stampidine或STAMP]，作为最有效的广谱非杀精子抗HIV剂。针对非B包膜亚型的临床HIV-1分离株，STAMP的效力比STV/d4 T高100倍，比齐多夫定（ZDV/AZT）高2倍。STAMP在亚纳摩尔至低纳摩尔浓度下抑制基因型和表型核苷类似物逆转录酶抑制剂（NRTI）耐药和非核苷（NNRTI）耐药HIV-1分离株的体外复制。在Hu-PBL-SCID小鼠中，经口给予STAMP对基因型和表型NRTI耐药临床HIV-1分离株表现出显著的剂量依赖性体内抗HIV活性（BR/92/019）。单次50 mg/kg口服推注剂量或4周STAMP治疗疗程产生的STAMP治疗浓度高于其IC 50值>4-log，并在猫免疫缺陷病毒（FIV）感染的猫中表现出有效的抗逆转录病毒活性。在高达500 mg/kg的剂量水平下，STAMP治疗与任何临床或实验室毒性证据无关。STAMP在小鼠、犬和猫中以硬明胶胶囊的形式经口给予配制的GMP级STAMP（25-100 mg/kg/天）后表现出有利的药代动力学行为。STAMP作为一种非杀精子的杀微生物剂具有特殊的临床用途，可防止细胞相关HIV-1从受感染的精液向女性生殖道的性传播。STAMP的进一步发展可能为旨在预防多药耐药HIV-1性传播的新战略提供基础。该I期提案的目标是：（i）在阴道HIV-1感染的Hu-PBL-SCID小鼠中检查含STAMP的凝胶制剂的杀微生物活性;和（ii）用于AIDS性传播的阴道FIV感染的猫模型。具体目标1和2可能为STAMP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，而不具有避孕功能。

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 that are currently being investigated are directed mainly at preventing pregnancy as well as protection against sexually transmitted diseases. The availability of a non-spermicidal microbicide is equally important 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. In a systematic effort to identify a broad-spectrum anti-HIV microbicide potentially capable of preventing the sexual transmission of HIV without affecting fertility, we have synthesized a series of phenyl phosphate derivatives of stavudine (STV/d4T) and identified stavudine-5'-(p-bromophenyl methoxyalaninyl phosphate) [Stampidine or STAMP], as the most potent broad-spectrum non-spermicidal anti-HIV agent. STAMP was 100-fold more potent than STV/d4T and 2-fold more potent than zidovudine (ZDV/AZT) against clinical HIV-1 isolates of non-B envelope subtype. STAMP inhibited the in vitro replication of genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor (NRTI)-resistant and non-nucleoside (NNRTI)-resistant HIV-1 isolates at subnanomolar to low nanomolar concentrations. Orally administered STAMP exhibited significant and dose-dependent in vivo anti-HIV activity in Hu-PBL-SCID mice against a genotypically and phenotypically NRTI-resistant clinical HIV-1 isolate (BR/92/019). A single 50 mg/kg oral bolus dose or a 4-week treatment course with STAMP yielded therapeutic concentrations of STAMP >4-logs higher than its IC50 value and exhibited potent antiretroviral activity in feline immunodeficiency virus (FlV)-infected cats. STAMP therapy was not associated with any clinical or laboratory evidence of toxicity at dose levels as high as 500 mg/kg. STAMP exhibited favorable pharmacokinetic behavior in mice, dogs, and cats following oral administration of formulated GMP-grade STAMP (25-100 mg/kg/day) as hard gelatin capsules. STAMP has particular clinical utility as a non-spermicidal microbicide to prevent sexual transmission of cell-associated HIV-1 from infected semen to the female genital tract. The further development of STAMP may provide the basis for a new strategy aimed at prevention of the sexual transmission of multidrug-resistant HIV-1. The goals of this Phase I proposal are: (i) to examine the microbicidal activity of STAMP-containing gel formulation in vaginal HIV-1 infected Hu-PBL-SCID mouse; and (ii) vaginal FIV-infected cat models for sexual transmission of AIDS. Specific Aims 1 and 2 may provide the foundation for the clinical development of STAMP in Phase II studies as a safe, effective broad-spectrum anti-HIV microbicide without conception-inhibiting functions.