| Structural highlights
Function
[CHIT1_HUMAN] Degrades chitin, chitotriose and chitobiose. May participate in the defense against nematodes and other pathogens. Isoform 3 has no enzymatic activity.[1] [2] [3]
Publication Abstract from PubMed
This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC50 values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150x against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma.
Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma.,Mazur M, Olczak J, Olejniczak S, Koralewski R, Czestkowski W, Jedrzejczak A, Golab J, Dzwonek K, Dymek B, Sklepkiewicz PL, Zagozdzon A, Noonan T, Mahboubi K, Conway B, Sheeler R, Beckett P, Hungerford WM, Podjarny A, Mitschler A, Cousido-Siah A, Fadel F, Golebiowski A J Med Chem. 2018 Feb 8;61(3):695-710. doi: 10.1021/acs.jmedchem.7b01051. Epub, 2018 Jan 11. PMID:29283260[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Boot RG, Renkema GH, Strijland A, van Zonneveld AJ, Aerts JM. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J Biol Chem. 1995 Nov 3;270(44):26252-6. PMID:7592832
- ↑ Renkema GH, Boot RG, Muijsers AO, Donker-Koopman WE, Aerts JM. Purification and characterization of human chitotriosidase, a novel member of the chitinase family of proteins. J Biol Chem. 1995 Feb 3;270(5):2198-202. PMID:7836450
- ↑ Boot RG, Renkema GH, Verhoek M, Strijland A, Bliek J, de Meulemeester TM, Mannens MM, Aerts JM. The human chitotriosidase gene. Nature of inherited enzyme deficiency. J Biol Chem. 1998 Oct 2;273(40):25680-5. PMID:9748235
- ↑ Mazur M, Olczak J, Olejniczak S, Koralewski R, Czestkowski W, Jedrzejczak A, Golab J, Dzwonek K, Dymek B, Sklepkiewicz PL, Zagozdzon A, Noonan T, Mahboubi K, Conway B, Sheeler R, Beckett P, Hungerford WM, Podjarny A, Mitschler A, Cousido-Siah A, Fadel F, Golebiowski A. Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma. J Med Chem. 2018 Feb 8;61(3):695-710. doi: 10.1021/acs.jmedchem.7b01051. Epub, 2018 Jan 11. PMID:29283260 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01051
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