Identification of novel macrocyclic peptidase substrates via on-bead enzymatic cyclization.
Peptidase-catalyzed formation of macrocyclic lactams on solid phase identifies ring systems that are favorably bound in the enzyme active site. We evaluated several cyclic peptide motifs linked by ester bonds between the P2 and P1' or the P1 and P2' side chains. The depsipeptide represented by structure 5 was readily generated by a variety of peptidases from precursor omega-amino acids or omega-amino esters. This strategy for identifying ring systems for potential macrocyclic transition state analogues was demonstrated with the serine peptidases trypsin and chymotrypsin, with the aspartic peptidase pepsin, and with the zinc peptidase thermolysin.
Center for New Directions in Organic Synthesis Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.
Kristina K
KK
Hansen
Henrik C
HC
Hansen
Ryan C
RC
Clark
Paul A
PA
Bartlett
D000577:Amides / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry; D001665:Binding Sites; D003500:Cyclization; D004150:Dipeptidases / Q000737:chemistry; D007769:Lactams / Q000138:chemical synthesis*; D008956:Models, Chemical; D010447:Peptide Hydrolases / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry; D013379:Substrate Specificity; D013820:Thermolysin / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
D000577:Amides; D000596:Amino Acids; D007769:Lactams; D010456:Peptides, Cyclic; D010447:Peptide Hydrolases; D004150:Dipeptidases; D012697:Serine Endopeptidases; D016282:Aspartic Acid Endopeptidases; D013820:Thermolysin; D015032:Zinc