Discovery and Optimization of Long-Acting, Unimolecular Peptide Triple Agonists of the GLP-1, GIP, and Glucagon Receptors
Patrick Knerr
Senior Director & Site Head, Novo Nordisk Research Center Indianapolis
Concurrent activation of the GLP-1, GIP, and glucagon receptors imparts combinatorial metabolic benefits in preclinical models of diabetes and obesity through multiple pharmacological mechanisms. Unimolecular peptide triple agonists were rationally designed and optimized via sequence mutation and fatty acylation to exhibit potent agonistic activities at all three receptors and preclinical extension of time-action predicting once-weekly clinical administration. Chronic treatment of obese rodents with a balanced triple agonist exhibited weight lowering efficacy superior to GLP-1 receptor mono-agonist semaglutide and GLP-1/GIP receptor co-agonist tirzepatide, without erosion of glycemic control. Furthermore, dose escalation of this triple agonist over six weeks of chronic treatment achieved body weight normalization in obese rodents, resulting in an average weight loss of approximately 60%. These profound pre-clinical results highlight the potential of this poly-pharmacological strategy as a powerful means to combat the obesity epidemic.
Patrick Knerr is the Senior Director & Site Head of the Novo Nordisk Research Center Indianapolis (NNRCI), an interdisciplinary team focused on the discovery and maturation of disruptive research concepts for the treatment of cardiometabolic and rare diseases. After completing his PhD in peptide natural products with Wilfred van der Donk at the University of Illinois in Urbana-Champaign, Pat held a position with the former DuPont Crop Protection (now FMC) before moving to the NNRCI in 2016 to rekindle his passion in peptide medicinal chemistry. He has driven a portfolio of drug discovery projects centered on peptide poly-agonists for the treatment of metabolic diseases, resulting in three active clinical/preclinical programs and six filed international patent applications, and was promoted to Site Head in early 2022.