The Paramyxo- and Pneumoviridae families include many pathogens (e.g., parainfluenza (HPIV3), respiratory syncytial (RSV), Hendra (HeV), and Nipah (NiV) viruses) that negatively impact global human health. Despite the demand for therapeutics to combat these pathogens, few effective treatment options are clinically available. Infection by these viruses requires fusion of the viral and cell membranes, a process mediated by a trimeric fusion glycoprotein (F). Inhibition of this process has emerged as a compelling strategy for the development of novel antiviral therapeutics. The trimeric F is initially displayed on the outer viral envelope in a metastable pre-fusion conformation. Once triggered, F undergoes a series of conformational changes that first extend the molecule to allow for insertion of a hydrophobic fusion peptide (FP) into the target cell membrane and then refold the trimeric assembly into an energetically stable post-fusion state, a process that drives the merger of the viral and host cell membranes. In collaboration with Moscona and Porotto labs at Columbia University Medical Center, we are developing peptides and peptide-mimics that inhibit infection by interfering with the structural transitions of the trimeric F assembly.