TY - JOUR
T1 - Peptide–Bismuth Bicycles
T2 - In Situ Access to Stable Constrained Peptides with Superior Bioactivity
AU - Voss, Saan
AU - Rademann, Jörg
AU - Nitsche, Christoph
N1 - Publisher Copyright:
© 2021 Wiley-VCH GmbH
PY - 2022/1/21
Y1 - 2022/1/21
N2 - Constrained peptides are promising next-generation therapeutics. We report here a fundamentally new strategy for the facile generation of bicyclic peptides using linear precursor peptides with three cysteine residues and a non-toxic trivalent bismuth(III) salt. Peptide–bismuth bicycles form instantaneously at physiological pH, are stable in aqueous solution for many weeks, and much more resistant to proteolysis than their linear precursors. The strategy allows the in situ generation of bicyclic ligands for biochemical screening assays. We demonstrate this for two screening campaigns targeting the proteases from Zika and West Nile viruses, revealing a new lead compound that displayed inhibition constants of 23 and 150 nM, respectively. Bicyclic peptides are up to 130 times more active and 19 times more proteolytically stable than their linear analogs without bismuth.
AB - Constrained peptides are promising next-generation therapeutics. We report here a fundamentally new strategy for the facile generation of bicyclic peptides using linear precursor peptides with three cysteine residues and a non-toxic trivalent bismuth(III) salt. Peptide–bismuth bicycles form instantaneously at physiological pH, are stable in aqueous solution for many weeks, and much more resistant to proteolysis than their linear precursors. The strategy allows the in situ generation of bicyclic ligands for biochemical screening assays. We demonstrate this for two screening campaigns targeting the proteases from Zika and West Nile viruses, revealing a new lead compound that displayed inhibition constants of 23 and 150 nM, respectively. Bicyclic peptides are up to 130 times more active and 19 times more proteolytically stable than their linear analogs without bismuth.
UR - http://www.scopus.com/inward/record.url?scp=85120869061&partnerID=8YFLogxK
U2 - 10.1002/anie.202113857
DO - 10.1002/anie.202113857
M3 - Article
SN - 1433-7851
VL - 61
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 4
M1 - e202113857
ER -