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| - Thia Zip Reaction for Synthesis of Large Cyclic Peptides: Mechanisms and Applications
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| - This paper describes the mechanism and application of an efficient thia zip cyclization that involvesa series of intramolecular rearrangements in a cysteine-rich peptide for the synthesis of large end-to-end cyclicpeptides. Key functional groups required in this reaction include an Nα-cysteine, a thioester, and at least oneinternal free thiol in a peptide. The zip reaction is initiated by intramolecular transthioesterification through aninternal thiol with the thioester. A thiolactone is formed under ring−chain tautomeric equilibrium that favorsring formation in aqueous buffered solution at pH > 7. Successive ring expansions through thiol−thiolactoneexchanges in the direction of the amino terminus lead finally to a large Nα-amino thiolactone which thenundergoes a spontaneous and irreversible ring contraction through a sequence-independent S to N acylisomerization to form an end-to-end lactam. The reversible thiolactone exchanges are sequence-dependent,and the rate-determining steps are shown by rate studies on model peptides. The assistance of internal thiolsin reducing the ring sizes and hence the entropy of the thiolactone exchanges correlates well with cyclizationrates. Zip-assisted end-to-end cyclizations forming 93- and 99-atom rings through a series of small thiolactoneintermediates were 60−200-fold faster under strongly denaturing conditions such as 8 M urea than thecorresponding unassisted lactamization. The thia zip reaction has been applied successfully to the synthesis ofa 31-amino acid cyclic peptide, the naturally occurring cyclopsychotride that shows the antimicrobial activity.In addition, the thia zip reaction also enables the synthesis of an engineered cyclic 33-amino acid animaldefensin by replacing the end-to-end disulfide with a lactam, which retains the antimicrobial activities of thenative open-chain form.
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