mRNA display: from basic principles to macrocycle drug discovery

Drug Discov Today. 2014 Apr;19(4):388-99. doi: 10.1016/j.drudis.2013.10.011.

Kristopher Josephson ¹, Alonso Ricardo ¹, Jack W Szostak ²

Affiliations

1 Ra Pharmaceuticals, One Kendall Square, Suite B14301, Cambridge, MA 02139, USA.
2 Howard Hughes Medical Institute, Department of Molecular Biology, and Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 617-726-5981, USA. Electronic address: szostak@molbio.mgh.harvard.edu.

PMID: 24157402 DOI: 10.1016/j.drudis.2013.10.011

Abstract

We describe a new discovery technology that uses mRNA-display to rapidly synthesize and screen macrocyclic peptide libraries to explore a valuable region of chemical space typified by Natural Products. This technology allows high-affinity peptidic macrocycles containing modified backbones and unnatural side chains to be readily selected based on target binding. Success stories covering the first examples of these libraries suggest that they could be used for the discovery of intracellular protein-protein interaction inhibitors, highly selective Enzyme inhibitors or synthetic replacements for monoclonal Antibodies. The review concludes with a look to the future regarding how this technology might be improved with respect to library design for cell permeability and bioavailability.

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