Christian W. Gruber
Medical University of Vienna, Center for Physiology and Pharmacology, Schwarzspanierstr. 17, 1090 Vienna, Austria

Peptides are highly diverse signaling molecules that regulate numerous physiological processes, primarily through G protein-coupled receptors (GPCRs) – the largest class of cell surface receptors and a major drug target family. Despite their therapeutic potential, peptide-based drugs for GPCRs have been hampered by poor metabolic stability, low oral bioavailability, and off-target effects due to limited receptor selectivity. To overcome these limitations, we harness biodiversity-driven resources – including animal venom peptides, plant defense peptide libraries, and invertebrate peptide hormones – to discover novel GPCR ligands that target human neuropeptide signaling systems based on their evolutionary similarity. Through peptidomics discovery (including mining of large genetic datasets) and functional/biological screening, we have identified receptor ligands with enhanced subtype selectivity and biased signaling profiles. Advanced methods such as de novo design, cyclization, and late-stage modifications have yielded stabilized peptide candidates, particularly for the κ-opioid receptor. Lead compounds demonstrate analgesic efficacy in vivo and represent promising candidates for treating chronic abdominal pain and inflammatory diseases.

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