A novel strategy for in vitro selection of peptide-drug conjugates.
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.
Li
Shuwei
S
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Roberts
Richard W
RW
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
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