ABSTRACT The rising obesity rate across all age groups underlines the dramatic increase in the incidence of diabetes in the United States. According to CDC, 34.2 million people or 10.5% of U.S. population have diabetes in 2018, with an estimated total cost of $327 billion to the healthcare system. The medical community has recognized that diabetes treatments should ideally lead to both blood glucose control and bodyweight loss. The mission of Transira Therapeutics is to develop an innovative best-in-class oral peptide drug for the treatment of the diabetes and obesity using our proprietary peptide stapling chemistry. The goal of this project is to develop a chemically modified peptide dual agonist of GIPR/GLP-1R as a once-daily oral drug for the treatment of diabetes and obesity. In our preliminary studies, we identified two stapled peptides that show biased dual GIP and GLP-1 receptor agonists along with the drastically improved proteolytic stability and robust in vivo glucose- lowering efficacy. In this SBIR phase I application, we have two specific aims: (1) Synthesis and evaluation of the chimeric GIPR/GLP-1R peptide dual agonists containing a lipid-modified chemical stapler for improved oral bioavailability; and (2) Preclinical assessment of the pharmacokinetics, glucose control, bodyweight reduction, and other metabolic effects of the orally administered GIPR/GLP-1R peptide dual agonist in DIO mice. We expect to identify one fatty diacid-containing biaryl-stapled peptide that exhibits Papp value >100 times greater than semaglutide (with a permeation enhancer if necessary) in the Caco-2 cell monolayer transport assay and glucose-lowering efficacy greater than or equal to semaglutide in oral glucose tolerance test (OGTT). Also, we expect the lipid-containing stapled peptide to show greater oral bioavailability than oral semaglutide, >25% decrease in fasting glucose levels in intraperitoneal glucose tolerance test (IPGTT), and >20% bodyweight reduction after PO administration compared to placebo in DIO mice. The successful completion of the phase I studies should lay a solid foundation for the IND-enabling phase II studies in the future.