Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides.
The naturally-occurring cyclic cystine-knot microprotein trypsin inhibitors MCoTI-I and MCoTI-II have been synthesised using both thia-zip native chemical ligation and a biomimetic strategy featuring chemoenzymatic cyclisation by an immobilised protease. Engineered analogues have been produced containing a range of substitutions at the P1 position that redirect specificity towards alternative protease targets whilst retaining excellent to moderate affinity. Furthermore, we report an MCoTI analogue that is a selective low-microM inhibitor of foot-and-mouth-disease virus (FMDV) 3C protease, the first reported peptide-based inhibitor of this important viral enzyme.
Thongyoo
Panumart
P
Department of Chemistry, Imperial College London, Exhibition Road, London, SW7 2AZ.
Roqué-Rosell
Núria
N
Leatherbarrow
Robin J
RJ
Tate
Edward W
EW
D032701:Biomimetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D047169:Cyclotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D010447:Peptide Hydrolases / Q000187:drug effects; D010940:Plant Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015202:Protein Engineering; D013997:Time Factors
D047169:Cyclotides; D008024:Ligands; C409922:MCoTI-I protein, Momordica cochinchinensis; D010940:Plant Proteins; D011480:Protease Inhibitors; C409923:trypsin inhibitor MCoTI-II; D010447:Peptide Hydrolases