Novel Pharmaceuticals in Appetite Regulation: Exploring emerging gut peptides and their pharmacological prospects

Abstract

Obesity, a global health challenge, necessitates innovative approaches for effective management. Targeting gut peptides in the development of anti-obesity pharmaceuticals has already demonstrated significant efficacy. Ghrelin, peptide YY (PYY), cholecystokinin (CCK), and amylin are crucial in appetite regulation offering promising targets for pharmacological interventions in obesity treatment using both peptide-based and small molecule-based pharmaceuticals. Ghrelin, a sole orexigenic gut peptide, has a potential for anti-obesity therapies through various approaches, including endogenous ghrelin neutralization, ghrelin receptor antagonists, ghrelin O-acyltransferase, and functional inhibitors. Anorexigenic gut peptides, peptide YY, cholecystokinin, and amylin, have exhibited appetite-reducing effects in animal models and humans. Overcoming substantial obstacles is imperative for translating these findings into clinically effective pharmaceuticals. Peptide YY and cholecystokinin analogues, characterized by prolonged half-life and resistance to proteolytic enzymes, present viable options. Positive allosteric modulators emerge as a novel approach for modulating the cholecystokinin pathway. Amylin is currently the most promising, with both amylin analogues and dual amylin and calcitonin receptor agonists (DACRAs) progressing to advanced stages of clinical trials. Despite persistent challenges, innovative pharmaceutical strategies provide a glimpse into the future of anti-obesity therapies.

Keywords: amylin; anti‐obesity pharmaceuticals; cholecystokinin; ghrelin; gut peptides; peptide YY.

FIGURE 1

Hormonal regulation of the hypothalamic melanocortin system. The function of MC4R is influenced by orexigenic AgRP/NPY neurons, which inhibit it, and anorexigenic POMC neurons, which stimulate it. Gut peptides, such as ghrelin, PYY, and GLP‐1, as well as other factors, for example, leptin, modulate AgRP/NPY and POMC activity impacting food intake. AgRP/NPY are stimulated by ghrelin and inhibited by PYY, GLP‐1 (indirectly), and leptin. POMC are stimulated by GLP‐1 and leptin, while ghrelin indirectly inhibits it., , There are conflicting reports on PYY's direct effect on POMC,, while the precise effects of amylin are still under investigation. AgRP, agouti‐related peptide; GABA, gamma‐aminobutyric acid; GLP‐1, glucagon‐like peptide‐1; MC4R, melanocortin‐4 receptor; NPY, neuropeptide Y; POMC, proopiomelanocortin; PYY, peptide YY; α‐MSH, α‐melanocyte‐stimulating hormone.