RT Inhibitor CSIC and Entry Inhibitor Retrocyclin RC101 as Microbicides

RT 抑制剂 CSIC 和进入抑制剂 Retrocyclin RC101 作为杀微生物剂

基本信息

批准号：
8317579
负责人：
Phalguni GUPTA
金额：
$ 173.29万
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 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8317579
关键词：
Animal Model Antiviral Agents Applications Grants Cells Cervical Development Drug Formulations Evaluation Goals HIV HIV-1 Human In Vitro Inflammation Laboratories Local Microbicides Macaca Modeling Monkeys Mucous Membrane Organ Culture Techniques Pharmacologic Substance Physiological Prevention Property Reverse Transcription Safety Satellite Viruses Silicone Elastomers Site Study models Technology Testing Tissues Toxic effect Toxicity Tests U-Series Cooperative Agreements Vagina Vaginal Ring Woman base controlled release design efficacy testing in vivo industry partner inhibitor/antagonist innovation interdisciplinary approach microbicide multidisciplinary non-nucleoside reverse transcriptase inhibitors novel novel strategies preclinical study programs retrocyclin safety testing simian human immunodeficiency virus transmission process viral resistance

项目摘要

This U19 Cooperative Agreement grant application is designed to perform preclinical studies to optimize a combination microbicide composed of the HIV-1 entry inhibitor retrocyclin RC101 and the nonnucleoside reverse transcriptase inhibitor (NNRTI) 5-chloro-3-phenylsulfonylindole-2-carboxamide (CSIC). Our goal is to develop a microbicide that will have potent anti-HIV activity against cell-free and cell-associated virus while inducing minimal viral resistance, be non-toxic and non-inflammatory to cervical and vaginal tissues and be safe and effective against vaginal SHIV challenge in monkeys. An optimal combination of RC-101 and CSIC with these properties will be chosen based on a highly interactive approach between four projects and two cores. Together, we will employ an array of in vitro and ex vivo laboratory tests of efficacy and toxicity, in vivo safety and efficacy tests in monkey models, and studies to optimize a silicone elastomer ring formulation of our compounds. The 4 projects of this grant application are: 1) Development of CSIC as a microbicide (Project 1, Dr. Parniak), 2) RC-101 as an intravaginal anti-HIV-1 topical microbicide (Project 2, Dr. Cole), 3) Testing candidate microbicides for antiviral activity and toxicity in a cervical tissue based organ culture (Project 3, Dr. Gupta), and 4) Evaluation of toxicity and efficacy of CSIC and RC-101 in monkeys (Project 4, Dr. Marx). The scientific studies in these four projects will be supported by the Administrative Core (Core A, Dr. Gupta) and a Formulation Core (Core B, Drs. Rohan and Smith). Dr. Tom Smith (Auritec Pharmaceuticals), serving as the Industry partner in this U19 program, will bring controlled release pellet technologies to develop vaginal ring delivery of RC-101- and CSIC-based microbicides in monkeys. In designing the scope of the proposed topical microbicide program, we have focused on extensively evaluating safety and toxicity of candidate microbicides utilizing in vitro studies, tissue explants and animal models, as well as an expanded and innovative organ culture model to study the antiviral activity of microbicides in the presence of common STIs. Our multidisciplinary approach to microbicide development targets two different sites of HIV-1 replication (entry and reverse transcription) through a controlled-release ring formulated product, utilizes a novel ex vivo organ culture to test toxicity, inflammation and antiviral activity across cervicovaginal mucosa, and applies macaque models to study toxicity and efficacy. Therefore, the proposed study will provide novel strategies to develop microbicides for the prevention of HIV-1 transmission and their sequelae for women.

该 U19 合作协议拨款申请旨在进行临床前研究，以优化由 HIV-1 进入抑制剂逆环素 RC101 和非核苷逆转录酶抑制剂 (NNRTI) 5-氯-3-苯磺酰吲哚-2-甲酰胺 (CSIC) 组成的组合杀菌剂。我们的目标是开发一种杀微生物剂，该杀微生物剂对无细胞和细胞相关病毒具有有效的抗 HIV 活性，同时诱导最小的病毒抵抗力，对宫颈和阴道组织无毒且无炎症，并且对阴道组织安全有效猴子的 SHIV 挑战。将基于四个项目和两个核心之间的高度交互方法来选择具有这些特性的 RC-101 和 CSIC 的最佳组合。我们将共同进行一系列体外和离体实验室功效和毒性测试、猴子模型的体内安全性和功效测试，以及优化我们化合物的有机硅弹性体环配方的研究。本次拨款申请的 4 个项目是：1) CSIC 作为杀微生物剂的开发（项目 1，Parniak 博士），2) RC-101 作为阴道内抗 HIV-1 局部杀微生物剂（项目 2，Cole 博士）， 3) 在基于宫颈组织的器官培养物中测试候选杀菌剂的抗病毒活性和毒性（项目 3，Gupta 博士），以及 4) 评估 CSIC 的毒性和功效和猴子中的 RC-101（项目 4，马克思博士）。这四个项目的科学研究将得到行政核心（核心 A，古普塔博士）和配方核心（核心 B，罗汉和史密斯博士）的支持。 Tom Smith 博士（Auritec Pharmaceuticals）作为该 U19 项目的行业合作伙伴，将带来控释颗粒技术，在猴子身上开发基于 RC-101 和 CSIC 的杀菌剂的阴道环递送。在设计拟议的局部杀菌剂计划的范围时，我们重点利用体外研究、组织外植体和动物模型以及扩展和创新的器官培养模型来广泛评估候选杀菌剂的安全性和毒性，以研究其抗病毒活性。存在常见性传播感染时使用杀微生物剂。我们的杀微生物剂开发多学科方法通过控释环配方产品针对 HIV-1 复制的两个不同位点（进入和逆转录），利用新型离体器官培养物来测试宫颈阴道粘膜的毒性、炎症和抗病毒活性，以及应用猕猴模型来研究毒性和功效。因此，拟议的研究将为开发杀菌剂以预防女性 HIV-1 传播及其后遗症提供新策略。