title: A novel strategy for in vitro selection of peptide-drug conjugates.
abstract: The chemical diversity of peptide and protein libraries generated from biological display systems is typically confined to the 20 naturally occurring amino acids. Here, we have developed a general strategy to introduce non-natural side chains into mRNA-display libraries via specific chemical derivatization. We constructed a mRNA-display library containing 3 x 10(12) different peptides bearing a pendant penicillin moiety in a fixed position. In vitro selection using this hybrid peptide-drug library resulted in novel inhibitors of the Staphylococcus aureus penicillin binding protein 2a (PBP2a). This strategy resulted in a penicillin-peptide conjugate that has at least 100-fold higher activity than the parent penicillin itself. Our approach provides a convenient way to enhance the efficacy of known drugs and facilitates the discovery of powerful new hybrid ligands with functionalities beyond those provided by the 20 naturally occurring residues.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Shuwei
authors.initials: S
authors.lastname: Li
authors.forename: Richard W
authors.initials: RW
authors.lastname: Roberts
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D006602:Hexosyltransferases / Q000737:chemistry; D002267:Muramoylpentapeptide Carboxypeptidase / Q000737:chemistry; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D046915:Penicillin-Binding Proteins; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry*; D010458:Peptidyl Transferases / Q000737:chemistry; D012333:RNA, Messenger / Q000737:chemistry; D013211:Staphylococcus aureus / Q000737:chemistry; D018440:beta-Lactam Resistance
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D019151:Peptide Library; D010455:Peptides; D012333:RNA, Messenger; D010397:Penicillanic Acid; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase