Structure-based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin.

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Andersen OA, Nathubhai A, Dixon MJ, Eggleston IM, van Aalten DM

Structure-based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin.

Chem Biol. 2008 Mar;15(3):295-301. doi: 10.1016/j.chembiol.2008.02.015.

PubMed ID

18355729 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Endochitinase B1	Q873X9	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Argifin	Chitotriosidase-1	IC 50 (nM)	4.50E+03	5.5	N/A	Details