Design of nature-inspired stabilized peptides for GPCR drug discovery

Neuropeptides are the most diverse class of signaling molecules with crucial roles for human health and disease. Most of these peptides act as hormones or as neurotransmitters via G protein-coupled receptors (GPCRs). GPCRs represent the largest family of cell surface receptors encoded by the human genome and they have been exploited as drug targets for many years. In fact, drugs that target these receptors account for ~30% of the global market share of therapeutics.
The development of peptide therapeutics targeting GPCRs has been limited by poor pharmacokinetics (metabolic instability, short half-life, and rapid clearance) and lack of oral bioavailability (low gastrointestinal stability and membrane permeability). Furthermore, the pharmacological concepts of biased signaling, receptor selectivity and allosterism need to be implemented into successful GPCR drug discovery projects to avoid harmful off-target effects.
To tackle these challenges, we explore genomes/transcriptomes to identify evolutionary-related human neuropeptides and utilize pharmacology-guided screening of nature-derived peptide extracts to discover novel GPCR ligands. Using state-of-the-art chemical and computational tools such as molecular grafting, backbone cyclization, cysteine stapling and de novo design, we have been developing innovative ligands for the k-opioid and cannabinoid-type 2 receptors that exhibit enhanced stability, and improved pharmacodynamic properties. As proof-of-concept, two lead candidates were analyzed in vivo for their analgesic and anti-inflammatory properties, which may be drug candidates for the treatment of chronic abdominal pain or inflammatory conditions.