Structure-based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin.
Journal - Chemistry & biology (England )
Chitinase inhibitors have chemotherapeutic potential as fungicides, pesticides, and antiasthmatics. Argifin, a natural product cyclopentapeptide, competitively inhibits family 18 chitinases in the nanomolar to micromolar range and shows extensive substrate mimicry. In an attempt to map the active fragments of this large natural product, the cyclopentapeptide was progressively dissected down to four linear peptides and dimethylguanylurea, synthesized using a combination of solution and solid phase peptide synthesis. The peptide fragments inhibit chitinase B1 from Aspergillus fumigatus (AfChiB1), the human chitotriosidase, and chitinase activity in lung homogenates from a murine model of chronic asthma, with potencies ranging from high nanomolar to high micromolar inhibition. X-ray crystallographic analysis of the chitinase-inhibitor complexes revealed that the conformations of the linear peptides were remarkably similar to that of the natural product. Strikingly, the dimethylguanylurea fragment, representing only a quarter of the natural product mass, was found to harbor all significant interactions with the protein and binds with unusually high efficiency. The data provide useful information that could lead to the generation of drug-like, natural product-based chitinase inhibitors.
|ISSN : ||1074-5521|
|Mesh Heading : ||Arginine Aspergillus fumigatus Biological Products Chitinase Crystallography, X-Ray Drug Design Oligopeptides Peptide Fragments Peptides, Cyclic Structure-Activity Relationship Urea analogs & derivatives metabolism pharmacology enzymology chemical synthesis metabolism chemistry metabolism chemical synthesis chemistry metabolism pharmacology metabolism pharmacology chemical synthesis metabolism analogs & derivatives metabolism pharmacology|
|Mesh Heading Relevant : ||chemistry pharmacology antagonists & inhibitors chemistry pharmacology|
Natural product family 18 chitinase inhibitors.
Journal - Natural product reports (England )
|ISSN : ||0265-0568|
|Mesh Heading : ||Acetylglucosamine Chitinase Dipeptides Disulfides Molecular Structure Peptides, Cyclic Proline Trisaccharides Tyrosine Xanthines chemical synthesis pharmacology chemical synthesis pharmacokinetics pharmacology chemistry chemical synthesis pharmacokinetics pharmacology chemistry chemistry chemical synthesis pharmacology chemistry pharmacology|
|Mesh Heading Relevant : ||Biological Factors Enzyme Inhibitors analogs & derivatives antagonists & inhibitors chemical synthesis pharmacology chemical synthesis pharmacology chemical synthesis pharmacology chemical synthesis pharmacology analogs & derivatives chemical synthesis|
Screening-based Discovery and Structural Dissection of a Novel Family 18 Chitinase Inhibitor*
Journal - Journal of Biological Chemistry
Family 18 chitinases play key roles in the life cycles of avariety of organisms ranging from bacteria to man. Very recentlyit has been shown that one of the mammalian chitinases is highlyoverexpressed in the asthmatic lung and contributes to the pathogenicprocess through recruitment of inflammatory cells. Althoughseveral potent natural product chitinase inhibitors have beenidentified, their chemotherapeutic potential or their use ascell biological tools is limited due to their size, complexchemistry, and limited availability. We describe a virtual screening-basedapproach to identification of a novel, purine-based, chitinaseinhibitor. This inhibitor acts in the low micromolar (Ki = 2.8± 0.2 µM) range in a competitive mode. Dissectionof the binding mode by x-ray crystallography reveals that thecompound, which consists of two linked caffeine moieties, bindsin the active site through extensive and not previously observedstacking interactions with conserved, solvent exposed tryptophans.Such exposed aromatics are also present in the structures ofmany other carbohydrate processing enzymes. The compound exhibitsfavorable chemical properties and is likely to be useful asa general scaffold for development of pan-family 18 chitinaseinhibitors.The atomic coordinates and structure factors (code 2IUZ) havebeen deposited in the Protein Data Bank, Research Collaboratoryfor Structural Bioinformatics, Rutgers University, New Brunswick,NJ (http://www.rcsb.org/).* The costs of publication of this article were defrayed in partby the payment of page charges. This article must thereforebe hereby marked "advertisement" in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.1 Supported by a British Biomedical Research Support Group CASEstudentship together with Syngenta.2 Supported by a Wellcome Trust studentship.