Chitotriosidase-1 Research Articles

Development of Dual Chitinase Inhibitors as Potential New Treatment for Respiratory System Diseases

Acidic mammalian chitinase (AMCase) and chitotriosidase-1 (CHIT1) are two enzymatically active proteins produced by mammals capable of cleaving the glycosidic bond in chitin. Based on the clinical findings and animal model studies, involvement of chitinases has been suggested in several respiratory system diseases including asthma, COPD, and idiopathic pulmonary fibrosis. Exploration of structure-activity relationships within the series of 1-(3-amino-1H-1,2,4-triazol-5-yl)-piperidin-4-amines, which was earlier identified as a scaffold of potent AMCase inhibitors, led us to discover highly active dual (i.e., AMCase and CHIT1) inhibitors with very good pharmacokinetic properties. Among them, compound 30 was shown to reduce the total number of cells in bronchoalveolar lavage fluid of mice challenged with house dust mite extract after oral administration (50 mg/kg, qd). In addition, affinity toward the hERG potassium channel of compound 30 was significantly reduced when compared to the earlier reported chitinase inhibitors.

CSF chitinase proteins in amyotrophic lateral sclerosis

ObjectiveTo evaluate the classifier performance, clinical and biochemical correlations of cerebrospinal fluid (CSF) levels of the chitinase proteins Chitotriosidase-1 (CHIT1), Chitinase-3-like protein 1 (CHI3L1) and Chitinase-3-like protein 2 (CHI3L2) in...

Human Chitinases: Structure, Function, and Inhibitor Discovery.

Chitinases are glycosyl hydrolases that hydrolyze the β-(1-4)-linkage of N-acetyl-D-glucosamine units present in chitin polymers. Chitinases are widely distributed enzymes and are present in a wide range of organisms including insects, plants, bacteria, fungi, and mammals. These enzymes play key roles in immunity, nutrition, pathogenicity, and arthropod molting. Humans express two chitinases, chitotriosidase 1 (CHIT1) and acid mammalian chitinase (AMCase) along with several chitinase-like proteins (CLPs). Human chitinases are reported to play a protective role against chitin-containing pathogens through their capability to degrade chitin present in the cell wall of pathogens. Now, human chitinases are gaining attention as the key players in innate immune response. Although the exact mechanism of their role in immune response is not known, studies in recent years begin to relate chitin recognition and degradation with the activation of signaling pathways involved in inflammation. The roles of both CHIT1 and AMCase in the development of various diseases have been revealed and several classes of inhibitors have been developed. However, a clear understanding could not be established due to complexities in the design of the right experiment for studying the role of human chitinase in various diseases. In this chapter, we will first outline the structural features of CHIT1 and AMcase. We will then review the progress in understanding the role of human chitinases in the development of various diseases. Finally, we will summarize the inhibitor discovery efforts targeting both CHIT1 and AMCase.

Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase

ObjectiveTo investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers.MethodsThe neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic...

Chitotriosidase - a putative biomarker for sporadic amyotrophic lateral sclerosis

BackgroundPotential biomarkers to aid diagnosis and therapy need to be identified for Amyotrophic Lateral Sclerosis, a progressive motor neuronal degenerative disorder. The present study was designed to identify the factor(s) which are differentially expressed in the cerebrospinal fluid (CSF) of patients with sporadic amyotrophic lateral sclerosis (SALS; ALS-CSF), and could be associated with the pathogenesis of this disease.ResultsQuantitative mass spectrometry of ALS-CSF and control-CSF (from orthopaedic surgical patients undergoing spinal anaesthesia) samples showed upregulation of 31 proteins in the ALS-CSF, amongst which a ten-fold increase in the levels of chitotriosidase-1 (CHIT-1) was seen compared to the controls. A seventeen-fold increase in the CHIT-1 levels was detected by ELISA, while a ten-fold elevated enzyme activity was also observed. Both these results confirmed the finding of LC-MS/MS. CHIT-1 was found to be expressed by the Iba-1 immunopositive microglia.ConclusionElevated CHIT-1 levels in the ALS-CSF suggest a definitive role for the enzyme in the disease pathogenesis. Its synthesis and release from microglia into the CSF may be an aligned event of neurodegeneration. Thus, high levels of CHIT-1 signify enhanced microglial activity which may exacerbate the process of neurodegeneration. In view of the multifold increase observed in ALS-CSF, it can serve as a potential CSF biomarker for the diagnosis of SALS.