Discovery and characterization of novel cysteine-rich peptides in medicinal plants

Abstract

Small molecules and proteins represent two major families of pharmaceuticals used clinically. In between these two families, in terms of molecular size, are the disulfide-constrained peptides, a class of compounds that have their drug-like advantages of both small molecules and proteins. Disulfide-constrained peptides share the advantages of proteins for high on-target specificity and low off-target adverse side effects. They also have the robustness of small molecules to tolerate thermal, chemical and enzymatic degradation. Currently, naturally-occurring constrained peptides in plants are an underexplored chemical space in drug discovery. The objective of my thesis is the discovery and characterization of novel cysteine-rich peptides in medicinal plants. They include Lycium babarum, the plant which produces wolfberries, the popular functional food and herb, from which a novel carboxypeptidase inhibitor and a new class of cysteine-rich peptides, lybatides containing a disulfide-stapled helix, were isolated. The wolfberry carboxypeptidase inhibitor inhibits the activity of carboxypeptidase A comparable to the potato carboxypeptidase inhibitor and may account for the anti-thrombotic effect usually associated to wolfberry. In contrast, lybatides isolated from the root bark of the same tree display a structure of naturally-occurring stapled peptides. This shows that one plant is able to produce different cysteine-rich peptides. In Eurycoma longifolia, commonly known as Tongkat Ali a popular aphrodisiac in Malaysia, a novel 10C-heveinlike peptide, elongtide 1, was isolated and characterized. The structure and disulfide connectivity of eL1 was determined, confirming the previously predicted disulfide connectivity of the 10C-hevein-like peptide subclass. Together, my thesis expands the existing knowledge of cysteine-rich peptides and enriches the number of existing disulfide-constrained peptide scaffolds for drug design and peptidyl therapeutic development.