Insight on the Order of Regioselective Ultrafast Formation of Disulfide Bonds in (Antimicrobial) Peptides and Miniproteins

Angew Chem Int Ed Engl. 2021 Sep 15. doi: 10.1002/anie.202107861. Online ahead of print.


<p class="Abstract" style="margin: 0cm 0cm 30pt; text-align: justify; line-height: 11.25pt; font-size: 8pt; font-family: Arial, sans-serif; caret-color: rgb(0, 0, 0); color: rgb(0, 0, 0);"><span lang="EN-US">Disulfide-rich peptides and proteins are among the most fascinating bioactive molecules. The difficulties associated with the preparation of these targets prompted the development of various chemical strategies. Nevertheless, the production of these targets remains very challenging or elusive. Recently, we introduced a strategy for one-pot disulfide bonds formation, tackling most of the previous limitations. Nevertheless, the effect of the order of oxidation remains an underexplored issue. Here we report on the synthetic flexibility and the full rainbow of oxidation orders of three disulfide bonds in targets that lack the knot motif. In contrast, our study reveals an essential order of disulfide bond formation in the EETI-II knotted miniprotein. This synthetic strategy was straightforwardly applied for the synthesis of novel analogues of the plectasin antimicrobial peptide with enhanced activities against methicillin-resistant&nbsp;<italic>Staphylococcus</italic>&nbsp;<italic>aureus (MRSA)</italic>, a notorious human pathogen.<o:p></o:p></span></p>.

PMID:34524726 | DOI:10.1002/anie.202107861