Obesity and diabetes are major public health concerns. Incretin-like therapeutics have proven highly effective in treating both conditions and their associated complications. We are exploring the next generation of higher efficacy compounds through biased signaling of cAMP over ß-arrestin on both GLP-1R and GIPR. Our findings demonstrate that biased agonists provide longer-lasting glucose reduction, greater food intake suppression, and weight loss, highlighting their potential in treating these conditions.

We describe here the design and development of potent peptide analogs that are completely refractory to hydrolytic enzyme action while retaining full biological activity, potency, and efficacy.  This lecture will describe the fundamental design principles, molecular pharmacology, and in vivo data detailing, fine tuning such activity by simple chemical modification of peptides. Some of the compounds described rival or better those used in the clinic.

We describe the characterization of a novel long-acting peptide agonist for GLP-1, GIP, Amylin, and Calcitonin, receptors (PTT-A) and assessed its efficacy against the dual GIPR/GLP-1R agonist Tirzepatide. PTT-A decreased blood glucose and calcium levels acutely in lean rodents and dose-dependently reduced cumulative food intake. Chronic studies in diet-induced obesity (DIO) rats showed that PTT-A led to substantial reductions in body weight and cumulative food intake, primarily by decreasing fat mass while preserving muscle mass, unlike tirzepatide. The tetra-agonist peptide demonstrated robust efficacy for glucose and plasma lipid lowering, insulin sensitization, and liver benefits, outperforming Tirzepatide at equivalent doses.

I will present on the development of small molecule agonist versions of peptides that bind G protein-coupled receptors (GPCRs) such as GLP-1R that play a role in obesity.

Small molecule modulators for the GLP1 receptor offer complementary chemical tools and therapeutic agents as a novel mode of action. We pioneered the discovery and development of a non-peptide and orally available small molecule GLP1 receptor agonist and an utterly novel action of the GLP1 peptide sensitizer. This represents a novel opportunity for the GLP1 receptor and Class B GPCRs as therapeutics to treat metabolic diseases in the future.

I present work completed in the Christian Heinis laboratory as part of my graduate studies where we developed synthesis and screening tools for generating large chemical libraries of small cyclic peptides, enabling the discovery of target-specific, orally bioavailable peptides. This generalizable workflow, applicable to interactions with a functional readout, yielded sub-1 kDa peptides with high-affinity binding to proteases and good oral bioavailability in rats.

Cyclic peptides have long been considered attractive as a drug modality due to their medium size and combining the advantages of small molecules and biologics. However, membrane permeability remains a significant challenge. Recently, physics-based Generative AI has emerged as a promising technology to design cyclic peptides with specific properties in mind. Here we focus on applying this method to design de novo cyclic peptides with drug-like oral bioavailability.

Although once considered highly infeasible, oral administration of peptide drugs is now a reality, as evidenced by oral semaglutide (Rybelsus) and oral octreotide (Mycapssa) drug products. In this presentation, we will discuss formulation strategies (and peptide design rules) to enable the oral absorption of both high solubility/low permeability peptides and low solubility/high permeability peptides, with an emphasis on early drug discovery.