Kasugamycin Is a Novel Chitinase 1 Inhibitor with Strong Antifibrotic Effects on Pulmonary Fibrosis

Pulmonary fibrosis is a devastating lung disease with few therapeutic options. CHIT1 (chitinase 1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through the regulation of TGF-β (transforming growth factor-β) signaling and effector function. Therefore, CHIT1 is a potential therapeutic target for pulmonary fibrosis. This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis. Extensive screening of small molecule libraries identified the aminoglycoside antibiotic kasugamycin (KSM) as a potent CHIT1 inhibitor. Elevated concentrations of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In in vivo bleomycin- and TGF-β–stimulated murine models of pulmonary fibrosis, KSM showed impressive antifibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that KSM inhibits fibrotic macrophage activation, fibroblast proliferation, and myofibroblast transformation. Null mutation of TGFBRAP1 (TGF-β–associated protein 1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of KSM in in vivo lungs and in vitro fibroblasts responses. KSM inhibits the physical association between CHIT1 and TGFBRAP1, suggesting that the antifibrotic effect of KSM is mediated through regulation of TGFBRAP1, at least in part. These studies demonstrate that KSM is a novel CHIT1 inhibitor with a strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.

Correspondence and requests for reprints should be addressed to Chun Geun Lee, Box G-L, 185 Meeting Street, Providence, RI 02912. E-mail:
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*J.-H.L. and C.-M.L. contributed equally to this work.

Supported by the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) grants PO1 HL114501 (J.A.E.) and R01 HL115813 and RO1 HL155558 (C.G.L.), National Institute of General Medical Sciences (NIGMS) grant P20 GM103652 (C.-M.L.). This work was also partly supported by the Peer-Reviewed Medical Research Program of Department of Defense grant W81XWH2210041 (C.G.L.) and a research grant (GR5290824) (C.G.L.) from Corestem Inc. and Brown Biomedical Innovations to Impact (BBII) grant (C.G.L.) from Brown University.

Author Contributions: Conception and design: J.-H.L., C.-M.L., and C.G.L. Generation of experimental resources and data collection: J.-H.L., C.-M.L., M.-O.K., J.W.P., S.K., B.A., E.L.H., X.Y.P., and J.H.L. Analysis and interpretation: J.-H.L., C.-M.L., J.A.E., and C.G.L. Drafting the manuscript for important intellectual content: J.-H.L., J.A.E., and C.G.L.

This article has a data supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

Originally Published in Press as DOI: 10.1165/rcmb.2021-0156OC on June 9, 2022

Author disclosures are available with the text of this article at www.atsjournals.org.

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