Development of RC-101 as an Intravaginal Anti-HIV-1 Topical Microbicide

开发 RC-101 作为阴道内抗 HIV-1 局部杀菌剂

• 批准号: 7681867
• 负责人: ALEXANDER MICHAEL COLE
• 金额: $ 40.24万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681867
• 关键词: Affect; Attention; Binding; Bioavailable; Cells; Cervical; Coitus; Combined Modality Therapy; Complex; Development; Drug Formulations; Epithelial Cells; Epithelium; Erythrocytes; Evaluation; Exhibits; Film; Gel; Goals; HIV; HIV-1; Heterosexuals; Human; Immunologist; In Vitro; Infection; Intravaginal Administration; Knowledge; Liquid substance; Local Microbicides; Macaca nemestrina; Measures; Modeling; Monkeys; Mucous Membrane; Organ Culture Techniques; Peptides; Pharmaceutical Preparations; Physiological; Pilot Projects; Preclinical Testing; Prevention; Principal Investigator; Resistance; Route; Seminal Plasma; Sexual Partners; Sexual Transmission; Silicone Elastomers; Structure; Surface; Testing; Tissues; Toxic effect; U-Series Cooperative Agreements; Vagina; Vaginal Ring; Vaginal Route of Drug Administration; Work; absorption; analog; antimicrobial peptide; base; controlled release; cost; cytokine; cytotoxicity; design; empowered; in vivo; inhibitor/antagonist; interdisciplinary approach; lysine analog; male; microbicide; multidisciplinary; non-nucleoside reverse transcriptase inhibitors; novel; polypeptide; prevent; programs; prophylactic; rectal; retrocyclin; transmission process; vaccine development; vaginal fluid; vaginal microbicide; vaginal transmission

Sexual transmission through mucosal surfaces has been the most common route of HIV-1 spread throughout the world. Although much attention has been focused on vaccine development for HIV-1, progress has been slow and there is an urgent need to find alternative approaches, such as topical microbicides, to target the spread of HIV-1. In our search for novel compounds active against HIV-1, we discovered that the cyclic antimicrobial peptides called retrocyclins were potent inhibitors of HIV-1 replication. We have synthesized and tested the anti-HIV-1 activity of nearly 120 analogs of retrocyclin, and determined that the lysine analog RC-101 was best suited for development as a topical microbicide. RC-101 was shown to be active against R5 and X4 HIV-1, and acts by preventing the initiation of the fusion complex by binding the heptad repeat region 2 on gp41, precluding six helix bundle formation. RC-101 also exhibited little to no cytotoxicity or induction of proinflammatory cytokines in organotypic cervicovaginal epithelia and cervical organ culture, did not hemagglutinate red blood cells, was remarkably stable, and could be formulated into thin films for intravaginal application. Pilot studies with film-formulated RC-101 in five pigtail macaques revealed that the peptide was safe, exhibited no appreciable toxicity, and was associated with cervicovaginal epithelial cells. Based on our findings, we have formed several hypotheses about RC-101: a) RC-101 is stable and bioavailable, thus will likely function to inhibit HIV-1 infection in the vaginal mucosa, b) RC-101 (an entry/fusion inhibitor) and CSIC (a non-nucleoside reverse transcriptase inhibitor being developed by Project 1) have different mechanisms of action and thus their activities will be complementary in preventing HIV transmission, and c) RC-101, formulated as a controlled-release product, can provide long-term protection against heterosexual HIV-1 transmission. With assistance from a multidisciplinary team, we will test these hypotheses by 1) determining the broad spectrum efficacy, stability in biologic fluids and ability to induce HIV-1 resistance of RC-101, alone and in combination with CSIC, and 2) evaluating silicone elastomer ring-formulated RC-101, alone and in combination with CSIC, in organotypic cervicovaginal tissues and following topical vaginal administration in monkeys. These studies involve a highly collaborative and iterative approach to develop RC-101 in combination with CSIC as a ring-formulated intravaginal topical microbicide.

通过粘膜表面的性传播一直是HIV-1传播的最常见途径 全世界。尽管已经关注HIV-1的疫苗开发，但 进度很慢，迫切需要寻找替代方法，例如局部 微生物，以靶向HIV-1的扩散。在我们寻找活跃于HIV-1的新颖化合物时，我们 发现称为折叠蛋白的环状抗菌肽是HIV-1的有效抑制剂 复制。我们已经合成并测试了近120个类似物的腹膜蛋白的抗HIV-1活性，并且 确定赖氨酸类似物RC-101最适合作为局部菌心的发育。 RC-101 被证明对R5和X4 HIV-1具有活性，并通过防止融合复合物的启动起作用 通过结合GP41上的Heptad重复区域2，排除了六个螺旋束的形成。 RC-101也展出 几乎没有细胞毒性或诱导细胞型宫颈阴道上皮细胞因子和促炎性细胞因子和 宫颈器官培养，没有脱血细胞红细胞，非常稳定，可以是 配制成薄膜，用于阴道内应用。在五只辫子中对膜形成的RC-101进行试验研究 猕猴显示肽是安全的，没有明显的毒性，并且与 宫颈阴道上皮细胞。根据我们的发现，我们形成了有关RC-101的几个假设： a）RC-101是稳定且可生物利用的，因此可能会抑制阴道粘膜中的HIV-1感染， B）RC-101（入口/融合抑制剂）和CSIC（非核苷逆转录酶抑制剂为 项目1）具有不同的行动机制，因此他们的活动将是互补的 在防止艾滋病毒传播时，c）c）RC-101（以受控释放产品为准）可以提供 对异性HIV-1传播的长期保护。在多学科的协助下 团队，我们将通过1）确定广泛的疗效，生物学流体的稳定性来检验这些假设 以及单独并与CSIC结合使用RC-101的HIV-1抗性的能力，以及2）评估 硅酮弹性体环形成的RC-101，单独并与CSIC结合，在器官型中 宫颈阴道组织和猴子局部阴道给药后。这些研究涉及 高度协作和迭代的方法与CSIC结合使用为环形成了RC-101 阴道内局部菌心。