The cyclic dipeptide CI-4 [cyclo-(l-Arg-d-Pro)] inhibits family 18 chitinases by structural mimicry of a reaction intermediate.
Family 18 chitinases are attractive targets for the development of new inhibitors with chemotherapeutic potential against fungi, insects and protozoan/nematodal parasites. Although several inhibitors have been identified, these are based on complex chemistry, which hampers iterative structure-based optimization. Here we report the details of chitinase inhibition by the natural product peptide CI-4 [ cyclo -(L-Arg-D-Pro)], which possesses activity against the human pathogenic fungus Candida albicans, and describe a 1.7 A (0.17 nm) crystal structure of CI-4 in complex with the enzyme. The structure reveals that the cyclic dipeptide inhibits chitinases by structurally mimicking a reaction intermediate, and could, on the basis of its accessible chemistry, be a candidate for further optimization.
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D010940:Plant Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D015202:Protein Engineering; D012706:Serratia marcescens / Q000201:enzymology*; D014312:Trisaccharides / Q000737:chemistry / Q000494:pharmacology; D014961:X-Ray Diffraction
D010456:Peptides, Cyclic; D010940:Plant Proteins; D014312:Trisaccharides; C098401:cyclo(Arg-Pro); C054851:allosamidin; D002688:Chitinases; C094255:PLC-B protein, Phytolacca americana; D000117:Acetylglucosamine