A chemical space approach to discover novel antimicrobial peptides

The ?Chemical space? describes the ensemble of all possible chemical compounds, in particular those of interest as drugs for medical use, spanning from small organic molecules such as aspirin to large proteins such as antibodies. The concept of chemical space calls for considering every possible molecule beyond those already known.[1] We recently started to design cheminformatic tools to describe the chemical space of peptides and proteins using 3D-pharmacophores and molecular shape.[2] We have now expanded this computational approach to explore the chemical space of topologically diverse, multi-branched peptides such as peptide dendrimers[3] and polycyclic peptides.[4] Here I present our initial results in using the method to discover novel bicyclic peptides with antimicrobial activities. These novel bicyclic antimicrobial peptides (bcAMPs) efficiently target multidrug resistant <i>P. aeruginosa</i> and <i>P. aeruginosa</i> biofilms while showing low hemolysis activity and high serum stability.<br>References: <br>1. Reymond, J. L. The Chemical Space Project. Acc. Chem. Res. 2015, 48, 722-730.<br>2. Jin, X.; Awale, M.; Zasso, M.; Kostro, D.; Patiny, L.; Reymond, J. L. Pdb-Explorer: A Web-Based Interactive Map of the Protein Data Bank in Shape Space. BMC Bioinformatics 2015, 16, 339.<br>3. Stach, M.; Siriwardena, T. N.; Kohler, T.; van Delden, C.; Darbre, T.; Reymond, J. L. Combining Topology and Sequence Design for the Discovery of Potent Antimicrobial Peptide Dendrimers against Multidrug-Resistant Pseudomonas Aeruginosa. Angew. Chem., Int. Ed. 2014, 53, 12827-12831.<br>4. Bartoloni, M.; Jin, X.; Marcaida, M. J.; Banha, J.; Dibonaventura, I.; Bongoni, S.; Bartho, K.; Grabner, O.; Sefkow, M.; Darbre, T.; Reymond, J.-L. Bridged Bicyclic Peptides as Potential Drug Scaffolds: Synthesis, Structure, Protein Binding and Stability. Chemical Science 2015, 6, 5473-5490