Beyond GLP-1: underexplored peptide–receptor systems as the next frontier in drug discovery

The unprecedented clinical success of glucagon-like peptide-1 (GLP-1) receptor agonists has transformed the therapeutic landscape for obesity, diabetes, and cardiometabolic disease, while simultaneously reshaping long-standing perceptions of peptide-based therapeutics as biologically compelling but pharmacologically impractical. Importantly, GLP-1 is not exceptional in its underlying biology; rather, it exemplifies how endogenous peptide systems with pleiotropic signaling can be rendered clinically tractable through advances in peptide stabilization, pharmacokinetics, receptor bias, and dosing strategies. This review examines a broad spectrum of endogenous peptide–receptor systems that regulate metabolism, appetite, bone–muscle–fat crosstalk, neuroendocrine function, immune modulation, and tissue repair, yet lack approved therapeutic analogs. Across these systems, early clinical or translational setbacks were frequently interpreted as evidence of flawed biology rather than limitations in pharmacologic engineering, dosing paradigms, or endpoint selection. By synthesizing evidence across these domains, this review argues that the primary barriers to development have historically been technological and conceptual rather than biological. Modern advances in long-acting peptide design, biased agonism, receptor de-orphanization, and systems pharmacology fundamentally alter the risk–benefit calculus of these targets. The next-generation of transformative peptide therapeutics is therefore likely to emerge not from novel hormone discovery, but from the systematic rediscovery and reengineering of endogenous peptide–receptor systems long considered too complex to pursue.