title: mRNA display: from basic principles to macrocycle drug discovery.
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.
authors.affiliation: Ra Pharmaceuticals, One Kendall Square, Suite B14301, Cambridge, MA 02139, USA.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Josephson
authors.affiliation: Ra Pharmaceuticals, One Kendall Square, Suite B14301, Cambridge, MA 02139, USA.
authors.forename: Alonso
authors.initials: A
authors.lastname: Ricardo
authors.affiliation: 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.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Szostak
mesh_terms: D001688:Biological Products; D055808:Drug Discovery; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry*; D012333:RNA, Messenger / Q000737:chemistry*
chemical_list: D001688:Biological Products; D019151:Peptide Library; D010455:Peptides; D012333:RNA, Messenger