PROJECT SUMMARY ABSTRACT Preterm birth is a major medical problem resulting in disability and death for very preterm infants. Therapeutic approaches to manage preterm labor are off-label and ineffective. No tocolytic therapy in use today is satisfactory beyond 48 hours, and none is FDA approved. Preterm labor more often impacts African American women than their Caucasian counterparts and is exacerbated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which leads to preterm birth in COVID- 19 affected pregnancies. Our central hypotheses are that designed multi-ligand (DML) drugs to be generated in this research that target dysregulated pathways in preterm myometrium will provide a therapeutic benefit in cases of preterm labor while decreasing fetal exposure to the compounds, and that co-administration of the DML’s ‘constituent single entities’ will exhibit synergistic tocolysis. In addition to providing a potential synergistic benefit, we expect that our DMLs will be poorly transported across the placenta due to favorable pharmacokinetic properties of the DMLs, and thus will protect the fetus from exposure. Decreased placental transfer will improve dose-ranging for clinical benefit to prevent preterm labor. This research will justify novel DMLs as potential new tocolytics to prevent preterm birth. This proposal will generate novel DMLs using advanced Medicinal Chemistry techniques and will make extensive use of ex vivo and in vivo experimentation using both human and mouse tissue. The long term goal of this project is to generate first-in-class tocolytics that will delay or halt early labor and prevent preterm birth.