Christian Gruber
Assoc. Prof., Medical University of Vienna
Peptide-based approaches to GPCR drug discovery: novel κ-opioid receptor ligands for applications in inflammatory pain
Abstract
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and key regulators of physiological processes, making them prime targets for therapeutic intervention. Among them, opioid receptors play a central role in pain modulation, with the κ-opioid receptor (KOR) emerging as a promising target for the development of safer analgesics that avoid the addictive potential of traditional µ-opioid drugs. Despite their therapeutic potential, peptide-based GPCR ligands face challenges such as poor metabolic stability, short half-life, and low oral bioavailability, necessitating innovative drug design strategies.
To overcome these limitations, we integrate multiple approaches, including evolutionary peptide mining from genomes and transcriptomes, as well as pharmacology-guided screening of nature-derived peptide extracts, to identify novel GPCR ligands. Using advanced chemical and computational techniques - such as molecular grafting, backbone cyclization, cysteine stapling, and de novo design - we have engineered peptide ligands with improved stability and pharmacodynamic properties. Specifically, our work focuses on the development of next-generation KOR agonists with tailored signaling profiles to mitigate side effects and enhance therapeutic efficacy. As a proof-of-concept, lead candidates have demonstrated analgesic and anti-inflammatory effects in vivo, highlighting their potential for the treatment of chronic pain syndromes, including peripheral pain and inflammatory bowel disease.
Bio
Christian Gruber is research group leader and Associate Professor at the Medical University of Vienna (Austria). He studied Biochemistry at the University of Tübingen (Germany) and received a Ph.D. in Molecular Biosciences from The University of Queensland (Australia). His research focus to study biological function, structure-activity relationship and pharmacological mechanism of nature-derived peptides isolated from plants and invertebrates (e.g., peptide hormones, neuropeptides and peptide toxins), and the development of novel peptide therapeutics, especially as ligands of G protein-coupled receptors.
Further information: www.gruber-lab.com
For his research achievements he won several awards such as the EFMC Prize for a Young Medicinal Chemist in Academia, European Federation for Medicinal Chemistry (2017), Dr. Willmar Schwabe-Award, Society for Medicinal Plant and Natural Product Research (2014), IUPHAR Young Investigator Silver Award, International Union of Basic and Clinical Pharmacology (2014) and the Heribert-Konzett Award, Austrian Pharmacological Society (sponsored by Astra Zeneca, 2013)
He has memberships and functions in scientific organizations such as the Austrian Peptide Community (founder and co-chair), Herbal Medicinal Products Platform Austria (vice-president) and the “Max-Bergmann-Kreis” – German-speaking association to promote peptide chemistry research (member elect). He is Associate Editor of the British Journal of Pharmacology and Editorial Board Member of the Journal of Medicinal Chemistry.
As co-founder and chief scientific officer of Pepdura AB (www.pepdura.com), he is involved in translation and the development of stabilized peptides for applications as GPCR ligands.