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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

基本信息

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
项目类别：
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

项目摘要

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是HIV-1最常见的传播途径