Sexual transmission through mucosal surfaces has been the most common route of HIV-1 spread throughout the world. Although much attention has been focused on vaccine development for HIV-1, progress has been slow and there is an urgent need to find alternative approaches, such as topical microbicides, to target the spread of HIV-1. In our search for novel compounds active against HIV-1, we discovered that the cyclic antimicrobial peptides called retrocyclins were potent inhibitors of HIV-1 replication. We have synthesized and tested the anti-HIV-1 activity of nearly 120 analogs of retrocyclin, and determined that the lysine analog RC-101 was best suited for development as a topical microbicide. RC-101 was shown to be active against R5 and X4 HIV-1, and acts by preventing the initiation of the fusion complex by binding the heptad repeat region 2 on gp41, precluding six helix bundle formation. RC-101 also exhibited little to no cytotoxicity or induction of proinflammatory cytokines in organotypic cervicovaginal epithelia and cervical organ culture, did not hemagglutinate red blood cells, was remarkably stable, and could be formulated into thin films for intravaginal application. Pilot studies with film-formulated RC-101 in five pigtail macaques revealed that the peptide was safe, exhibited no appreciable toxicity, and was associated with cervicovaginal epithelial cells. Based on our findings, we have formed several hypotheses about RC-101: a) RC-101 is stable and bioavailable, thus will likely function to inhibit HIV-1 infection in the vaginal mucosa, b) RC-101 (an entry/fusion inhibitor) and CSIC (a non-nucleoside reverse transcriptase inhibitor being developed by Project 1) have different mechanisms of action and thus their activities will be complementary in preventing HIV transmission, and c) RC-101, formulated as a controlled-release product, can provide long-term protection against heterosexual HIV-1 transmission. With assistance from a multidisciplinary team, we will test these hypotheses by 1) determining the broad spectrum efficacy, stability in biologic fluids and ability to induce HIV-1 resistance of RC-101, alone and in combination with CSIC, and 2) evaluating silicone elastomer ring-formulated RC-101, alone and in combination with CSIC, in organotypic cervicovaginal tissues and following topical vaginal administration in monkeys. These studies involve a highly collaborative and iterative approach to develop RC-101 in combination with CSIC as a ring-formulated intravaginal topical microbicide.

Public Health Relevance

HIV-1 is most commonly spread through sexual contact at mucosal (e.g. vaginal) surfaces. We have discovered a novel compound called RC-101 that is active against HIV-1, and are working to develop this compound as a drug to prevent HIV-1 transmission. Availability of RC-101, in the form of an extended release vaginal ring, would empower vulnerable sexual partners by providing them with an effective means of protection.

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-BP-A (J1))
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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
Eade, Colleen R; Diaz, Camila; Chen, Sixue et al. (2015) HIV-Enhancing Factors Are Secreted by Reproductive Epithelia upon Inoculation with Bacterial Vaginosis-Associated Bacteria. Protein Pept Lett 22:672-80
Wood, Matthew P; Cole, Amy L; Eade, Colleen R et al. (2014) The HIV-1 gp41 ectodomain is cleaved by matriptase to produce a chemotactic peptide that acts through FPR2. Immunology 142:474-83
Wood, Matthew P; Cole, Amy L; Ruchala, Piotr et al. (2013) A compensatory mutation provides resistance to disparate HIV fusion inhibitor peptides and enhances membrane fusion. PLoS One 8:e55478
Eade, Colleen R; Cole, Amy L; Diaz, Camila et al. (2013) The anti-HIV microbicide candidate RC-101 inhibits pathogenic vaginal bacteria without harming endogenous flora or mucosa. Am J Reprod Immunol 69:150-8
Eade, Colleen R; Diaz, Camila; Wood, Matthew P et al. (2012) Identification and characterization of bacterial vaginosis-associated pathogens using a comprehensive cervical-vaginal epithelial coculture assay. PLoS One 7:e50106
Levinson, Pauline; Choi, Robert Y; Cole, Amy L et al. (2012) HIV-neutralizing activity of cationic polypeptides in cervicovaginal secretions of women in HIV-serodiscordant relationships. PLoS One 7:e31996
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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