The diversity in nature has long been and still is one of the biggest resources of pharmaceutical lead compounds and many natural products often exhibit biological activity against unrelated biological targets,1 thus providing us with starting points for pharmacological analysis. Natural peptides of great number and diversity occur in all organisms from plants to microbes to man. Examples for such rich and yet largely untapped libraries of bioactive compounds are animal venom peptides, invertebrate peptide hormones or plant defense peptides. Our goals are to discover and characterize novel bioactive peptides,4 screen their pharmacological activity, determine their structure-activity relationship and synthesize optimized peptide compounds to study ligand-receptor signaling.3
As proof-of-concept we have used a genome-mining approach or mass spectrometry to determine the occurrence and molecular structure of naturally-occurring oxytocin-like peptides and we have investigated their pharmacological profile on human oxytocin and vasopressin receptors. Plant cyclotides, insect inotocins2 and marine cone-snail conopressins5 have been identified as pharmacological probes to study receptor-subtype selectivity. Combining structure-activity analysis and peptide chemistry, we are aiming to generate selective, potent and stable peptide ligands that are potentially oral bioavailable and may be useful for the treatment of a wide range of challenging, but yet untreated diseases.