Peptide YY triagonist weight loss drugs

PROJECT SUMMARY The growing global epidemic of obesity poses a major public health concern. Obesity/excessive overweight is associated with a high risk of developing sequelae including type 2 diabetes, cardiovascular complications, neurodegeneration, and certain cancers. By 2017, the prevalence of obesity had risen to an alarming 41.9% in the United States, with profound implications on immediate medical costs in addition to a far greater overall economic burden, diminished quality of life, and premature mortality. Physiologically, body weight via modulation of appetite and energy expenditure is in large part regulated by enteroendocrine peptide hormones that act through both central nervous and peripheral mechanisms. One of these hormones, peptide YY3-36 (“PYY”) has long been recognized as an anorexic modulator but only recently, stable analogues have been engineered that can pharmacologically induce weight loss in animals. The underlying mechanisms are partially distinct from and synergize with those that are activated by two other enteroendocrine hormones, glucagon-like peptide-1 GLP1) and glucose-dependent insulinotropic peptide (GIP) which form the basis of the most successful weight loss drugs in the clinic today. Still, despite remarkable average efficacy across the population, many patients are non-responders to such drugs and quit treatment. In addition, induction of nausea and vomiting are frequent adverse effects that limit efficacy and compromise compliance. As a strategy to address these limitations, we propose to develop a novel weight loss drug that is centered on PYY as a different emphasis, but includes synergizing GLP1 and GIP function in a chimeric triagonist molecule that we were able to engineer as a starting point to explore this approach. In the proposed Phase I study, will transform this proof-of-concept triagonist into suitable leads for future exploration of therapeutic efficacy in a future Phase II follow-up. Toward this goal, Phase I will focus on tuning the potency balance of our triagonist at targeted receptors, with the objective of generating four leads that cover a set of profiles that is predicted to optimally exploit the benefits of PYY, GLP1, and GIP agonism while minimizing potential drug liabilities. Furthermore, leads will be further adjusted to confer compound stability against enzymatic degradation and extended serum half-life as required for therapeutically effective injections. These objectives will be pursued in an interdisciplinary collaboration between scientists in academia and biotechnology with expertise in medicinal chemistry, molecular pharmacology, and early in vivo studies. Although beyond the scope of the proposed Phase I proposal, the objective in an anticipated Phase II follow-up will be to investigate safety and efficacy of drug candidates to induce therapeutic weight loss in animals as the basis for IND enabling studies.