Development of CSIC as a Microbicide

抗艾滋病毒的局部杀微生物剂是一种可利用的手段，以尽量减少艾滋病毒的传播。某些艾滋病毒逆转 转录酶抑制剂（RTIs）是一种很有前途的杀菌剂候选物和基于NNRTI的杀菌剂 （UC 781和TMC 120）以及一种核苷酸RT抑制剂（PMPA;替诺福韦）正在进行1期临床试验。 审判然而，确实需要确定新的管道RTI作为备用杀微生物剂 众所周知，许多具有有希望的临床前性质的药物在高级临床评价期间失败。的 新型NNRTI 5-氯-3-（苯磺酰基）吲哚-2-甲酰胺（CSIC）可能是一个重要的管道 我们的初步数据表明，CSIC的体外杀微生物功效与 关于UC 781针对不同HIV靶点的联合杀微生物剂可能更可取，我们建议 CSIC和HIV进入抑制剂抗微生物肽RC-101的组合将提供上级 广谱抗艾滋病毒杀微生物活性。为此，我们提出以下具体目标： 项目内容：（1）评价CSIC单独和联合应用的体外杀菌性能。 （2）探讨CSIC诱导的保护性或“记忆”机制 （3）确定基于CSIC单独和与RC-101组合的杀微生物剂是否 体外选择传播NNRTI耐药病毒;（4）开发并验证分析方法 为了定量阴道或直肠局部给药后CSIC的血浆、细胞和组织水平， 猴子（项目4）。

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).