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).

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of Pittsburgh
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Gong, Tiantian; Zhang, Wei; Parniak, Michael A et al. (2017) Preformulation and Vaginal Film Formulation Development of Microbicide Drug Candidate CSIC for HIV prevention. J Pharm Innov 12:142-154
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Eade, Colleen R; Wood, Matthew P; Cole, Alexander M (2012) Mechanisms and modifications of naturally occurring host defense peptides for anti-HIV microbicide development. Curr HIV Res 10:61-72
Rinehart, Matthew T; Drake, Tyler K; Robles, Francisco E et al. (2011) Time-resolved imaging refractometry of microbicidal films using quantitative phase microscopy. J Biomed Opt 16:120510
Penberthy, W Todd; Chari, Soumya; Cole, Amy L et al. (2011) Retrocyclins and their activity against HIV-1. Cell Mol Life Sci 68:2231-42

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