ABSTRACT
Rationale Pulmonary fibrosis is a devastating lung disease with few therapeutic options. Chitinase 1 (CHIT1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through regulation of Transforming Growth Factor (TGF)-β signaling and effector function. Therefore, CHIT1 is a potential therapeutic target of pulmonary fibrosis.
Objectives This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis.
Methods Extensive screening of small molecule libraries identified the aminoglycoside antibiotic Kasugamycin as a potent CHIT1 inhibitor.
Measurements and Main Results Elevated levels of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In vivo bleomycin- and TGF-β-stimulated murine models of pulmonary fibrosis, Kasugamycin showed impressive anti-fibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that Kasugamycin inhibits fibrotic macrophage activation, fibroblast proliferation and myofibroblast transformation. Null mutation of transforming growth factor beta associated protein 1 (TGFBRAP1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of Kasugamycin in in vivo lungs and in vitro fibroblasts responses. Kasugamycin inhibits physical association between CHIT1 and TGFBRAP1 with decreased levels of SMAD4 association, suggesting that antifibrotic effect of Kasugamycin is mediated through regulation of TGFBRAP1, at least in part.
Conclusions These studies demonstrate that Kasugamycin is a novel CHIT1 inhibitor with strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.
Subject code 9.24 Interstitial Lung Disease
Competing Interest Statement
Jack A. Elias is a cofounder of Elkurt Pharmaceuticals that develops therapeutics based on the 18 glycosyl hydrolase gene family.
Footnotes
↵* Equal contribution to the work
Impact of this research on clinical medicine and basic science Idiopathic pulmonary fibrosis is a devastating lung disease with few therapeutic options. This study identified Kasugamycin as a chitinase 1 inhibitor with strong antifibrotic activity that can be developed as an effective and safe therapeutic drug for the patients with pulmonary fibrosis. This study also provides a novel mechanism that Kasugamycin uses to control fibrotic tissue and cellular responses in the lung.
Competing Interests Disclosures: Jack A. Elias is a cofounder of Elkurt Pharmaceuticals that develops therapeutics based on the 18 glycosyl hydrolase gene family.
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