Butelase‐Mediated Macrocyclization of d‐Amino‐Acid‐Containing Peptides. Issue 41 (14th September 2016)

• Record Type: Journal Article
• Authors: Nguyen, Giang K. T.; Hemu, Xinya; Quek, Jun‐Ping; Tam, James P.
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 41(2016)
• Page Start: 12802
• Page End: 12806
• Publication Date: 2016-09-14
• Subjects: d-amino acids -- antibiotics -- cyclization -- enzymes -- peptides; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201607188
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Macrocyclic compounds have received increasing attention in recent years. With their large surface area, they hold promise for inhibiting protein–protein interactions, a chemical space that was thought to be undruggable. Although many chemical methods have been developed for peptide macrocyclization, enzymatic methods have emerged as a promising new economical approach. Thus far, most enzymes have been shown to act onl ‐peptides; their ability to cyclized ‐amino‐acid‐containing peptides has rarely been documented. Herein we show that macrocycles consisting ofd ‐amino acids, except for the Asn residue at the ligating site, were efficiently synthesized by butelase 1, an Asn/Asp‐specific ligase. Furthermore, by using a peptide‐library approach, we show that butelase 1 tolerates most of thed ‐amino acid residues at the P1′′ and P2′′ positions. Abstract : d ‐elightfullyd ‐iverse : The broad tolerance of butelase 1, an Asn/Asp‐specific ligase, ford ‐amino‐acid‐containing peptides enabled the efficient synthesis of various peptide macrocycles with sequences derived from those of naturally occurring peptides (see scheme). Thed andl forms of the resulting macrocyclic peptides were evaluated for their antimicrobial activity and found to be broadly active against antibiotic‐resistant bacteria.