Potent inhibitors of beta-tryptase and human leukocyte elastase based on the MCoTI-II scaffold.
MCoTI-II is a member of a class of microproteins known as cyclotides that possess a macrolactam-cystine knot scaffold imparting exceptional physiological stability and structural rigidity. Modification of residues in the active loop and engineered truncations have resulted in MCoTI-II analogues that possess potent activity against two therapeutically significant serine proteases: beta-tryptase and human leukocyte elastase. These results suggest that MCoTI-II is a versatile scaffold for the development of protease inhibitors against targets in inflammatory disease.
Thongyoo
Panumart
P
Department of Chemistry and Chemical Biology Centre, Imperial College London SW7 2AZ, UK.
Bonomelli
Camille
C
Leatherbarrow
Robin J
RJ
Tate
Edward W
EW
D000595:Amino Acid Sequence; D047169:Cyclotides / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D013379:Substrate Specificity; D053802:Tryptases / Q000037:antagonists & inhibitors*
D047169:Cyclotides; D011480:Protease Inhibitors; C409923:trypsin inhibitor MCoTI-II; D019272:Leukocyte Elastase; D053802:Tryptases