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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合作协议授权申请旨在进行临床前研究，以优化由HIV-1进入抑制剂逆转录病毒素RC 101和非核苷逆转录酶抑制剂（NNRTI）5-氯-3-苯磺酰基吲哚-2-甲酰胺（CSIC）组成的组合杀微生物剂。我们的目标是开发一种杀微生物剂，该杀微生物剂将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耐药性，对宫颈和阴道组织无毒且无炎症，并且对猴阴道SHIV攻击安全有效。将根据四个项目和两个核心之间的高度互动方法选择具有这些特性的RC-101和CSIC的最佳组合。我们将共同采用一系列体外和离体实验室疗效和毒性测试、猴模型体内安全性和疗效测试以及优化我们化合物的硅橡胶弹性体环配方的研究。是次拨款申请的四个项目为：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，科尔博士），3）在基于宫颈组织的器官培养物中测试候选杀微生物剂的抗病毒活性和毒性（项目3，Dr. Gupta），和4）CSIC和RC-101在猴中的毒性和疗效评价（项目4，Dr.马克思）。这四个项目中的科学研究将得到管理核心（核心A，Gupta博士）和制剂核心（核心B，罗汉博士和史密斯博士）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，以开发基于RC-101和CSIC的杀微生物剂在猴子中的阴道环递送。在设计拟议的局部杀微生物剂计划的范围时，我们集中于利用体外研究、组织外植体和动物模型以及扩大的创新器官培养模型广泛评估候选杀微生物剂的安全性和毒性，以研究杀微生物剂在常见STI存在下的抗病毒活性。我们的杀微生物剂开发的多学科方法通过控释环制剂产品靶向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来测试宫颈阴道粘膜的毒性，炎症和抗病毒活性，并应用猕猴模型来研究毒性和疗效。因此，拟议的研究将提供新的战略，开发杀微生物剂，预防艾滋病毒-1传播及其后遗症的妇女。