In recent years, the development of bioorthogonal reactions has had a profound impact on several research areas such as imaging, drug development, biochemistry, and biotechnology. However, further advances in this topic are hindered by the limited number of biocompatible chemical transformations and by their rather modest reaction rate. BioMPCat (Bioorthogonal Metal-Peptide Catalysis) aims at overcoming the current limitations by establishing metal-peptide complexes as a novel and powerful class of bioorthogonal catalysts capable of promoting unprecedented transformations with remarkable efficiency under physiological conditions.
Naturally occurring peptides are ideally suited ligands for metals and, due to the inherent large structural and functional diversity, the chemical properties of their metal-complexes can be tuned to display optimal catalytic features: reactivity, selectivity, stability, and biocompatibility. Using simple and rationally designed combinatorial assays, the BioMPCat project focuses on the identification of lead catalysts structures for biomolecules ligations and as well as for site-selective cleavage of native proteins under physiological conditions.
The objectives of the action are the exploration on novel catalytic concepts: (1) identifying a non-toxic and highly effective Cu-peptide catalyst for the alkyne-azide cycloaddition reaction, which could render such important transformation compatible with the cellular environment; (2) developing a general approach to site-selective cleavage of native proteins. This research aims to investigate the interface between chemistry and biology: new perspectives in biochemistry and cell biology will be opened, as well as novel avenues in medicinal chemistry and therapeutics.
On this basis, from 1st March 2017 to 30th September 2017, the investigations within BioMPCat have focused on the identification of a new peptide ligand capable of stabilizing Cu(I) species under aerobic conditions and promoting the Cu-AAC with remarkable efficiency. Using split-and-mix peptidic libraries, convenient screening methods for the identification of functional peptides were designed. These experiments allowed the simultaneous testing of thousands of peptidic ligands and the identification of catalyst candidates. This process allowed the identification of a promising class of peptidic ligand for the desired transformation. The results constitute a milestone-proof of concept for the BioMPCat project and demonstrate the possible use of peptidic ligands in biorthogonal chemistry.
In conclusion, these initial results set the ground for future exploration in the field of bioorthogonal metal-peptide catalysis and constitute an interesting starting point for a thorough optimization of such peptidic ligands, which could lead to the identification of an optimal catalyst candidate.
