Investigating PYY3-36 and PYY3-36 analogues in the development of an obesity therapy

Obesity, defined as a body mass index greater than 30kg/m2, has reached the scale of a pandemic. The increasing prevalence of obesity, and its associated morbidity and mortality, together with limited treatment options, underscores an urgent need for effective therapeutic interventions. Gut hormones have been identified as integral factors in the regulation of appetite. One such gut hormone is Peptide YY (PYY), a postprandial satiety hormone that communicates nutritional status to the central nervous system. PYY is processed to generate the principle circulating form PYY3-36, which acts on Y2 receptors in the brainstem and hypothalamus to reduce appetite. Chronic intravenous infusion of PYY3-36 induces weight loss in rodents and acute intravenous infusion to obese humans reduces food intake. Furthermore, obese humans have been reported to display a blunted postprandial rise in PYY3-36, suggesting PYY3-36 is a potential anti-obesity drug target. However, exogenous PYY3-36 is rapidly cleared and has a short circulating half-life. Additionally, at supraphysiological levels PYY3-36 can produce nausea in humans. The administration of long-acting PYY3-36 analogues to the obese may overcome these limitations. This thesis investigates the design and development of PYY3-36 analogues, and their potential in the treatment of obesity. I have investigated modifications to different domains within the primary structure of PYY3-36 in order to elucidate Y2R affinity, susceptibility to proteolytic degradation and biological activity. I demonstrated that a combination of substitutions in different domains can create a long acting analogue. I have examined sites at which PYY3-36 is susceptible to degradation by specific proteases and identified that inhibition of meprin metalloendopeptidases can prolong the plasma longevity and anorectic actions of PYY3-36. I also found that substitution of a section of the α-helix of PYY3-36 with a conserved α-helical epitope creates a long-acting analogue, that is more efficacious than PYY3-36 in chronically reducing food intake and body weight in a diet-induced obese rodent model. Finally, in investigating a slow-release delivery system for PYY3-36 analogues, I have shown that substituting His residues into the α-helix-substituted analogue promotes chelation with Zn in vitro, and facilitates a slow-release pharmacokinetic profile in vivo, that may circumvent the side effects associated with administering high levels of PYY3-36