ABSTRACT Genital herpes simplex virus (HSV) infection is one of the most common sexually transmitted infections worldwide. The infection is lifelong: there currently is no cure and no vaccine. In addition, HSV-1 and -2, human papillomavirus (HPV), and human immunodeficiency virus (HIV) are responsible for intersecting epidemics, where the disease caused by one virus facilitates the transmission and/or pathogenesis of the other. Numerous studies suggest that user-controlled multipurpose products providing HSV prevention –ideally along with HPV and HIV– in combination with contraception would strongly motivate higher uptake relative to single-purpose products: women not self-identifying as at risk of HSV infection would use a multipurpose product to avoid pregnancy, resulting in significantly improved user compliance, and hence effectiveness, relative to single-purpose antiviral products. Many women would prefer a topical (vaginal) nonhormonal contraception method that, unlike vaginal gels, does not require use immediately before or after sex. Our application integrates key innovations in developing a next generation multipurpose technology (MPT) intravaginal ring (IVR) comprised of: (1) antiviral peptide lead candidate with activity against HSV, HPV, and HIV; (2) small-molecule inhibitors of sperm functions required to reach and fertilize the oocyte; and (3) a novel IVR platform for long-acting, controlled delivery of the two-drug combination. We have designed and synthesized a library of small antiviral peptides that disrupt a range of viruses, including HSV, HPV, and HIV, at low µM concentrations. An existing lead candidate, optimized for vaginal delivery, has been selected for IVR formulation under the current application. In parallel, we have designed and synthesized a library of highly potent, small-molecule inhibitors of soluble adenylyl cyclase (sAC) that effectively block sperm motility and prevent in vitro fertilization at sub nM concentrations. Finally, our team developed an innovative IVR platform for the delivery of drug combinations, including small molecules and biomolecules, at independently controlled rates. In Aim 1, we will evaluate our panel of sAC inhibitor late-lead candidates using biochemical, functional, and pharmacological assays to select a lead candidate designed specifically for vaginal dosing. In Aim 2, we will formulate and evaluate in vitro human-sized MPT IVRs to deliver our lead antiviral peptide and lead contraceptive combinations at target in vitro rates. In Aim 3, we will assess the pharmacokinetics and pharmacodynamics (safety and anti-HSV efficacy) of MPT IVR candidates in mice (efficacy and preliminary safety) and sheep (pharmacokinetics and safety). This project builds on an established collaboration of investigators and will advance our scientific knowledge on vaginal delivery of novel agents in the context of HSV prevention and nonhormonal contraception.