RT Inhibitor CSIC and Entry Inhibitor Retrocyclin RC101 as Microbicides

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retrocyclin RC101和非核苷类逆转录酶抑制剂（NNRTI） 5-氯-3-苯基磺酰基lindol -2-carboxamide （CSIC）组成的联合杀微生物剂。我们的目标是开发一种杀微生物剂，它将对无细胞病毒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和无炎症，并且安全有效地对抗猴阴道SHIV攻击。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。我们将共同进行一系列体外和离体实验室药效和毒性测试，在猴子模型中进行体内安全性和有效性测试，并研究优化我们化合物的有机硅弹性体环配方。该基金申请的4个项目是：1)开发CSIC作为杀微生物剂（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)在宫颈组织器官培养中测试候选杀微生物剂的抗病毒活性和毒性（项目3，Gupta博士），4)评估CSIC和RC-101在猴子中的毒性和有效性（项目4，Marx博士）。这四个项目的科学研究将由行政核心（核心A，古普塔博士）和配方核心（核心B，古普塔博士）支持。罗翰和史密斯)。Tom Smith博士（Auritec制药公司），作为U19项目的行业合作伙伴，将带来控释颗粒技术，用于开发基于RC-101和csic的杀微生物剂在猴子体内的阴道环递送。在设计拟议的局部杀微生物剂计划的范围时，我们专注于广泛评估候选杀微生物剂的安全性和毒性，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研究杀微生物剂在常见性传播感染中的抗病毒活性。我们的多学科杀菌剂开发方法通过控释环配方产品靶向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，本研究将为开发杀微生物剂提供新的策略，以预防HIV-1的传播及其对妇女的后遗症。

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.