Metabolic

Cagrilintide is a long-acting synthetic analogue of human amylin (islet amyloid polypeptide) developed by Novo Nordisk. It is a 37-amino acid acylated peptide engineered for once-weekly subcutaneous administration, contrasting with the native amylin half-life of approximately 13 minutes. Cagrilintide is in Phase 3 clinical development both as a standalone obesity treatment and as a component of CagriSema, a fixed-ratio combination with semaglutide. The combination approach (CagriSema) represents the most advanced amylin + GLP-1 RA strategy in clinical development. By targeting two complementary satiety pathways — amylin signaling through the area postrema and GLP-1 signaling through hypothalamic neurons — the combination has produced weight reductions exceeding 22% in Phase 3 trials, surpassing the efficacy of either component alone and approaching the range of metabolic surgery.

Melanotan II (MT-II) is a cyclic heptapeptide analogue of alpha-melanocyte-stimulating hormone (α-MSH) developed at the University of Arizona in the 1990s. It is a non-selective melanocortin receptor agonist that binds MC1R through MC5R, producing a range of physiological effects including skin pigmentation (tanning), sexual arousal, appetite suppression, and lipolysis. Melanotan II is the parent compound from which PT-141 (bremelanotide) was derived. Despite never receiving regulatory approval in any jurisdiction, Melanotan II has been widely available through grey-market suppliers and has been self-administered by a substantial number of individuals seeking tanning effects. This unregulated use has generated both clinical data (through case reports and surveillance) and safety concerns. The peptide's non-selective melanocortin receptor activity produces broader effects than the more targeted PT-141, which was specifically developed to isolate the MC4R-mediated sexual function effects while minimizing MC1R-driven pigmentation.

MOTS-c (Mitochondrial Open Reading Frame of the Twelve S rRNA Type-C) is a 16-amino acid peptide encoded within the mitochondrial genome, discovered in 2015 by Changhan Lee's group at USC. It is the first mitochondrial-derived peptide shown to function as a systemic signaling molecule, challenging the traditional view that mitochondria primarily encode structural and enzymatic components of the electron transport chain. MOTS-c represents a new class of retrograde signals from mitochondria to the nucleus that regulate metabolic homeostasis. MOTS-c circulates in blood and its levels respond to physiological stimuli — exercise increases circulating MOTS-c, while aging and metabolic disease are associated with declining levels. In preclinical models, exogenous MOTS-c administration prevents diet-induced obesity, improves insulin sensitivity, and reverses age-related physical decline. The peptide has generated significant research interest as a potential exercise mimetic and metabolic regulator, though no human clinical trials have been completed.

PT-141 (bremelanotide) is a cyclic heptapeptide melanocortin receptor agonist developed originally as a metabolite of Melanotan II. It was the first centrally-acting agent approved for hypoactive sexual desire disorder (HSDD) in premenopausal women, marketed as Vyleesi by Palatin Technologies/AMAG Pharmaceuticals and approved by the FDA in 2019. Unlike phosphodiesterase inhibitors (sildenafil, tadalafil) that act on peripheral vascular mechanisms, PT-141 acts directly on melanocortin-4 receptors (MC4R) in the hypothalamus to enhance sexual desire and arousal through central nervous system pathways. The peptide differs from its parent compound Melanotan II by the removal of the amino terminal and C-terminal amide, producing a metabolite that retains MC4R activity for sexual function while substantially reducing MC1R-mediated tanning effects. Its approval represented a paradigm shift in sexual medicine — from treating the mechanical aspects of sexual response to targeting the neural circuits underlying desire itself.

Retatrutide (LY-3437943) is a first-in-class triple agonist peptide that simultaneously activates the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. Developed by Eli Lilly, it represents an evolution beyond dual GIP/GLP-1 agonists like tirzepatide by incorporating glucagon receptor activation, which adds thermogenic energy expenditure and hepatic lipid metabolism to the weight loss and glycemic control mechanisms of incretin agonism. The peptide is a modified 39-amino acid chain with a C20 fatty diacid moiety that enables albumin binding and once-weekly dosing. As of 2024, it is in Phase 3 clinical trials for obesity and type 2 diabetes, with prior Phase 2 results generating substantial attention for producing the largest weight reductions seen in clinical trials at the time of publication.

Semaglutide is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) developed by Novo Nordisk. It is a 31-amino acid peptide analogue of human GLP-1 with two key modifications: an alpha-aminoisobutyric acid substitution at position 8 that confers resistance to dipeptidyl peptidase-4 (DPP-4) degradation, and a C18 fatty diacid chain attached to lysine at position 26 via a linker that enables non-covalent albumin binding, extending the half-life to approximately 7 days. Semaglutide is approved for type 2 diabetes (Ozempic, subcutaneous; Rybelsus, oral) and chronic weight management (Wegovy, subcutaneous). It is among the most commercially successful and clinically studied peptide therapeutics, with major outcomes trials demonstrating benefits in glycemic control, weight reduction, and cardiovascular risk reduction. The oral formulation (Rybelsus) represents a significant pharmaceutical achievement as the first oral GLP-1 RA, using a sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) absorption enhancer.