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.
Keywords: Macrocyclization, cyclic conotoxin, antimicrobial peptide, chemotaxis.
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