Development of CSIC as a Microbicide

CSIC作为杀菌剂的开发

基本信息

批准号：
7681866
负责人：
MICHAEL A PARNIAK
金额：
$ 23.46万
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/7681866
关键词：
Animals Antiviral Agents Basic Science Binding Biological CCR5 gene Cell membrane Cells Characteristics Clinical Data Dendritic Cells Development Drug Combinations Drug Formulations Engineering Epithelial Cells HIV HIV Entry Inhibitors HIV Infections HIV drug resistance HIV-1 Heterosexuals In Vitro Indoles Laboratories Legal patent Local Microbicides Lymphocyte Memory Methods Monkeys Mutation Nucleotides Patients Pharmaceutical Preparations Phase I Clinical Trials Plasma Preparation Property Publishing Refractory Resistance Reverse Transcriptase Inhibitors SIV Sampling Sexual Transmission Swab Tenofovir Tissues Topical application UC 781 Vagina Vaginal Douching Viral Virion Virus absorption analytical method anti-HIV microbicide antimicrobial peptide base cell type design experience inhibitor/antagonist interest macrophage member microbicide mutant non-nucleoside reverse transcriptase inhibitors novel peptide analog pinacolyl methylphosphonic acid pre-clinical prevent programs protective effect rectal research clinical testing research study resistance mutation retrocyclin topical antiviral transmission process vaginal microbicide

项目摘要

Anti-HIV topical microbicides are an accessible means to minimize HIV transmission. Certain HIV reverse transcriptase inhibitors (RTIs) are promising microbicide candidates and microbicides based on NNRTI's (UC781 and TMC120) as well as one with a nucleotide RT inhibitor (PMPA; tenofovir) are in Phase 1 clinical trials. However, there is a definite need to identify new pipeline RTI's as backup microbicidal agents as it is well known that many drugs with promising preclinical properties fail during advanced clinical evaluation. The novel NNRTI 5-chloro-3-(phenylsulfonyl)indole-2-carboxamide (CSIC) may represent an important pipeline drug as our preliminary data suggest that the in vitro microbicidal efficacy of CSIC is as good or superior to that of UC781. Combination microbicides directed at different HIV targets may be preferable and we propose that the combination of CSIC and the HIV entry inhibitor antimicrobial peptide RC-101 will provide superior broad spectrum anti-HIV microbicidal activity. In this context, we propose the following Specific Aims for this Program Project component: (1) To evaluate the in vitro microbicidal properties of CSIC alone and in combination with RC-101; (2) To determine the mechanism of the CSIC-induced protective or "memory" effect; (3) To determine whether microbicides based on CSIC alone and in combination with RC-101 will select in vitro for transmission of NNRTI-resistant virus; and (4)To develop and validate an analytical method to quantify the plasma, cellular and tissue levels of CSIC following vaginal or rectal topical administration in monkeys (Project 4).

抗艾滋病毒局部杀菌剂是减少艾滋病毒传播的一种可行方法。某些艾滋病毒逆转转录酶抑制剂 (RTI) 是有前途的候选杀菌剂和基于 NNRTI 的杀菌剂（UC781 和 TMC120）以及一种核苷酸 RT 抑制剂（PMPA；替诺福韦）正处于 1 期临床试验。然而，确实需要确定新的管道 RTI 作为备用杀菌剂。众所周知，许多具有良好临床前特性的药物在高级临床评估过程中失败了。这新型 NNRTI 5-氯-3-(苯磺酰基)吲哚-2-甲酰胺 (CSIC) 可能代表一个重要的管道我们的初步数据表明，CSIC 的体外杀菌功效与其他药物一样好或优于 UC781 的。针对不同 HIV 目标的组合杀微生物剂可能更可取，我们建议 CSIC 与 HIV 进入抑制剂抗菌肽 RC-101 的组合将提供卓越的效果广谱抗 HIV 杀菌活性。在此背景下，我们提出以下具体目标计划项目组成部分： (1) 评价单独使用 CSIC 和单独使用 CSIC 的体外杀菌特性。与RC-101组合； (2) 确定CSIC引起的保护或“记忆”的机制影响; (3) 确定基于CSIC的单独杀微生物剂以及与RC-101组合的杀微生物剂是否会选择体外传播 NNRTI 抗性病毒； (4)开发并验证分析方法定量阴道或直肠局部给药后血浆、细胞和组织中的 CSIC 水平猴子（项目 4）。