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

Mazur, Marzena; Dymek, Barbara; Koralewski, Robert; Sklepkiewicz, Piotr; Olejniczak, Sylwia; Mazurkiewicz, Marcin; Piotrowicz, Michał; Salamon, Magdalena; Jędrzejczak, Karol; Zagożdżon, Agnieszka; Czestkowski, Wojciech; Matyszewski, Krzysztof; Borek, Bartłomiej; Bartoszewicz, Agnieszka; Pluta, Elżbieta; Rymaszewska, Aleksandra; Mozga, Witold; Stefaniak, Filip; Dobrzański, Paweł; Dzwonek, Karolina; Gołąb, Jakub; Gołębiowski, Adam; Olczak, Jacek

doi:10.1021/acs.jmedchem.9b00681

Cited by 21 publications

(31 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, it was shown that inhibition of CHIT1 has more favorable therapeutic effects than nintedanib and comparable therapeutic efficiency to pirfenidone in the bleomycin-induced pulmonary fibrosis model ( 24 , 67 ). CHIT1 is recently considered as a novel therapeutic target in IPF and the first-in-class CHIT1 inhibitor is currently studied as a potential treatment for IPF ( 68 , 69 ). Based on our study’s novel finding that baseline serum CHIT1 activity could discriminate stables from progressors, we believe that CHIT1 could be useful as a potential biomarker of prognosis for the clinical practice in IPF, however further studies are warranted to confirm the present study results.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal and Comparative Measures of Serum Chitotriosidase and YKL-40 in Patients With Idiopathic Pulmonary Fibrosis

et al. 2022

View full text Add to dashboard Cite

BackgroundAlthough chitin is absent in humans, chitinases are present in healthy subjects and show dysregulated expression in a variety of diseases resulting from abnormal tissue injury and repair responses. It was shown that chitotriosidase (chitinase 1/CHIT1) and structurally-related chitinase 3-like 1 protein (CHI3L1/YKL-40) play important roles in the pathobiology of idiopathic pulmonary fibrosis (IPF), however little is known about their longitudinal serum levels and relationship to clinical measures in IPF.MethodsThe present study is the first to evaluate serial measurements of serum CHIT1 activity and YKL-40 concentrations in patients with IPF starting antifibrotic treatment and followed up for 24 months. In addition, baseline serum CHIT1 and YKL-40 were compared between patients with IPF and control subjects, and possible CHIT1 and YKL-40 relationships to longitudinal clinical assessments in IPF were explored.ResultsBaseline serum CHIT1 activity and YKL-40 concentrations were significantly elevated in patients with IPF compared to control subjects and showed similar discriminatory ability in distinguishing IPF from controls. No significant differences between the median serum CHIT1 activity and YKL-40 concentration measured over a study follow-up were noted. We found significantly elevated baseline serum CHIT1 activity in the progressors compared with the stables in the first year, while significantly increased baseline serum CHIT1 activity was noted in the stables compared to the progressors in the second year. Additionally, we observed a significant negative correlation between a change in serum YKL-40 concentration and a change in forced vital capacity (FVC) % predicted (% pred.) in the stables subgroup, whereas, a change in serum CHIT1 activity correlated negatively with a change in FVC% pred. in the progressors subgroup.ConclusionsThis explorative study findings add further evidence that CHIT1 and YKL-40 are upregulated in patients with IPF, and suggest that longitudinally stable serum CHIT1 activity and YKL-40 concentration levels may potentially be associated with the antifibrotic treatment response. In addition, our findings are supporting the possible role of CHIT1 and YKL-40 as candidate diagnostic and prognostic biomarkers in IPF. Further research is needed to validate present study findings.

show abstract

Section: Discussionmentioning

confidence: 99%

Longitudinal and Comparative Measures of Serum Chitotriosidase and YKL-40 in Patients With Idiopathic Pulmonary Fibrosis

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The other active chitinase in human tissue is acidic mammalian chitinase (AMCase), which has also been implicated in the pathogenesis of bronchial asthma and other inflammatory conditions [ 89 ]; however, it has never been studied in cystinosis. The recent development of selective chitotriosidase and dual chitinase inhibitors with very good safety profiles [ 87 , 90 ] may provide further hope to address inflammatory disorders in a pathway that may not cause harm to the kidneys. It would be interesting to see the actions of such inhibitors in inflammation-associated conditions primarily affecting the kidney, such as cystinosis.…”

Section: Future Perspectivesmentioning

confidence: 99%

Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies

Elmonem

Veys

Prencipe

2022

Cells

View full text Add to dashboard Cite

The activation of several inflammatory pathways has recently been documented in patients and different cellular and animal models of nephropathic cystinosis. Upregulated inflammatory signals interact with many pathogenic aspects of the disease, such as enhanced oxidative stress, abnormal autophagy, inflammatory cell recruitment, enhanced cell death, and tissue fibrosis. Cysteamine, the only approved specific therapy for cystinosis, ameliorates many but not all pathogenic aspects of the disease. In the current review, we summarize the inflammatory mechanisms involved in cystinosis and their potential impact on the disease pathogenesis and progression. We further elaborate on the crosstalk between inflammation, autophagy, and apoptosis, and discuss the potential of experimental drugs for suppressing the inflammatory signals in cystinosis.

show abstract

“…The already described argifin has an insecticide potential demonstrated in Periplaneta americana ( Omura et al, 2000 ). Furthermore, chitinase inhibitors can also be employed to relieve the symptoms of respiratory diseases, since chitinolytic activity and chitinase expression levels increases during pulmonary inflammations, aggravating it ( Létuvé et al, 2010 ; Mazur et al, 2019 ). For instance, the already described allosamidin was observed to reduce the asthma inflammatory process by reducing lymphocyte and eosinophil recruitment to mouse lungs ( Zhu et al, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

A Plumieridine-Rich Fraction From Allamanda polyantha Inhibits Chitinolytic Activity and Exhibits Antifungal Properties Against Cryptococcus neoformans

et al. 2020

View full text Add to dashboard Cite

Cryptococcosis is a fungal infection caused mainly by the pathogenic yeasts Cryptococcus neoformans and Cryptococcus gattii . The infection initiates with the inhalation of propagules that are then deposited in the lungs. If not properly treated, cryptococci cells can disseminate and reach the central nervous system. The current recommended treatment for cryptococcosis employs a three-stage regimen, with the administration of amphotericin B, flucytosine and fluconazole. Although effective, these drugs are often unavailable worldwide, can lead to resistance development, and may display toxic effects on the patients. Thus, new drugs for cryptococcosis treatment are needed. Recently, an iridoid named plumieridine was found in Allamanda polyantha seed extract; it exhibited antifungal activity against C. neoformans with a MIC of 250 μg/mL. To address the mode of action of plumieridine, several in silico and in vitro experiments were performed. Through a ligand-based a virtual screening approach, chitinases were identified as potential targets. Confirmatory in vitro assays showed that C. neoformans cell-free supernatant incubated with plumieridine displayed reduced chitinase activity, while chitinolytic activity was not inhibited in the insoluble cell fraction. Additionally, confocal microscopy revealed changes in the distribution of chitooligomers in the cryptococcal cell wall, from a polarized to a diffuse cell pattern state. Remarkably, further assays have shown that plumieridine can also inhibit the chitinolytic activity from the supernatant and cell-free extracts of bacteria, insect and mouse-derived macrophage cells (J774.A1). Together, our results suggest that plumieridine can be a broad-spectrum chitinase inhibitor.

show abstract

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

Cited by 21 publications

References 34 publications

Longitudinal and Comparative Measures of Serum Chitotriosidase and YKL-40 in Patients With Idiopathic Pulmonary Fibrosis

Longitudinal and Comparative Measures of Serum Chitotriosidase and YKL-40 in Patients With Idiopathic Pulmonary Fibrosis

Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies

A Plumieridine-Rich Fraction From Allamanda polyantha Inhibits Chitinolytic Activity and Exhibits Antifungal Properties Against Cryptococcus neoformans

Contact Info

Product

Resources

About