title: Macrocyclic Antimicrobial Peptides Engineered from ω-Conotoxin.
abstract: The potent calcium channel blocker ω-conotoxin MVIIA is a linear cystine-knot peptide with multiple basic amino acids at both termini. This work shows that macrocyclization of MVIIA linking two positive-charge terminal clusters as a contiguous segment converts a conotoxin into an antimicrobial peptide. In addition, conversion of disulfide bonds to amino butyric acids improved the antimicrobial activity of the cyclic analogs. Ten macrocyclic analogs, with or without disulfide bonds, were prepared by both Boc and Fmoc chemistry using native chemical ligation. All cyclic analogs were active against selected Gram-positive and Gram-negative bacteria with minimal inhibitory concentrations in a low μM range. In contrast, MVIIA and its linear analog were inactive at concentrations up to 0.5 mM. The cyclic analogs also showed 2 to 3-fold improved chemotactic activity against human monocytes THP-1 compared with MVIIA. Reduction of molecular stability against thermal and acid treatment due to the reduced number of disulfide crosslinks can be partly restored by backbone cyclization. Together, these results show that macrocyclization and side chain modification of a linear conopeptide lead to a gain-of-function, which brings a new perspective in designing and engineering of peptidyl therapeutics.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 03s-71, Singapore 637551, Singapore.
authors.forename: Xinya
authors.initials: X
authors.lastname: Hemu
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 03s-71, Singapore 637551, Singapore.
authors.forename: James P
authors.initials: JP
authors.lastname: Tam
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020916:Conotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000382:microbiology; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D064368:Healthy Volunteers; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D015202:Protein Engineering; D013329:Structure-Activity Relationship
chemical_list: D023181:Antimicrobial Cationic Peptides; D002121:Calcium Channel Blockers; D020916:Conotoxins; D047028:Macrocyclic Compounds
keywords: Macrocyclization; antimicrobial peptide; chemotaxis.; cyclic conotoxin