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.

The growth of peptide-based programs in drug discovery, and in particular those developed through mRNA display, has required the parallel development of new chemistries to enable access to non-canonical amino acids (ncAAs) and ultimately macrocyclic peptides. We describe our efforts to prepare a novel orally bioavailable PSCK9 inhibitor and how these approaches can be used to enable other peptide programs.

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.

Nisotirostide is a novel NPY2 receptor agonist designed to enhance the metabolic effects of GLP-1 receptor agonists in type 2 diabetes and obesity. In vitro studies showed selective activation of NPY2 receptor signaling, while in vivo studies demonstrated significant reductions in food intake and body weight in mice. Chronic administration in diet-induced obese mice resulted in dose-dependent weight loss and improved glucose homeostasis. These findings suggest that Nisotirostide has the potential to improve glycemic control and reduce body weight in patients with type 2 diabetes and obesity. Clinical evaluation is ongoing.

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.

The discovery of BMS-986238, a second-generation macrocyclic peptide and a potent inhibitor of PD-L1, is described. The targeted profile of this asset included the property of tight binding kinetics to the PD-L1 receptor, but with a significantly modified pharmacokinetic profile and specifically a long plasma half-life. These properties were predicted to reduce the frequency of QD-dosing as compared to the first-generation inhibitor BMS-986189 and likewise enable oral administration.

The GDF15-GFRaL-RET protein complex is involved in appetite control and is an attractive target for disease states such as obesity and cachexia. We describe the discovery of Bicycle peptides and the design of Bicycle tandems capable of mimicking the homodimeric GDF15 ligand and modulating the intracellular signaling response driven by the hexameric complex assembly.

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.

In macrocyclic peptide (MP) drug discovery, the ability to fine-tune structural features as well as physical chemical properties is crucial for developing drug-like candidates. Due to the limited availability of commercial non-canonical amino acids (ncAAs), the discovery of novel building blocks for these purposes is paramount. Late-stage functionalization (LSF) is a highly efficient strategy for identifying novel ncAAs but is restricted by the limited number of chemistries compatible with fully elaborated MPs. This presentation will highlight some of our recent accomplishments in expanding the LSF toolbox for MPs.