The development of gut hormones as drugs for the treatment of obesity

Abstract

Obesity is an ever-increasing problem with limited effective treatments available that are safe and tolerable. Gut hormones are naturally occurring endogenous satiety factors that are released in response to food consumption. As well as playing an important role in the regulation of appetite, food intake and body weight, they also have roles in glucose disposal, gastric motility, fuel-type utilisation and energy expenditure. These characteristics make gut hormones attractive drugable targets for the treatment of obesity. However, the vulnerability of gut hormones to degradative enzymes results in rapid clearance rates and limited bioactivity which limits their viability as anti-obesity therapies. This work aims to address two important properties to consider when developing gut hormones as drugs: cause of degradation and immunogenicity. Using pancreatic polypeptide (PP), I developed in vitro and in vivo testing systems to identify the physiologically important mechanisms involved in PP degradation. DPPIV and NEP were identified as important enzymes and enzyme-resistant analogues of PP were designed which demonstrated greater efficacy and slower clearance rates. Subcutaneous (SC) administration of foreign exogenous peptides is known to potentially cause immunogenic reactions against the foreign peptide. The dangers of this reaction can range from mild to lethal. Currently peptide therapeutics require SC administration as oral bioavailability is low. Therefore, an aim of my studies was to explore the impact of modifications to PYY with regard to immunogenicity. To do this I assessed the impact of changes to different regions and specific amino acids of PYY. I successfully identified a region of PYY which, when modified, caused immunogenicity and what substitutions resulted in the most changes to immunogenic properties. In summary, my work demonstrated that by understanding the causes of peptide clearance and immunogenicity, safer and more efficacious analogues of gut hormones can be designed to take forward as potential treatments for obesity.