Computational Screening Strategy for Drug Repurposing Identified Niclosamide as Inhibitor of Vascular Calcification

Frontiers in Cardiovascular Medicine

Cardiovascular Medicine

Takeshi Tanaka¹  Shiori Kuraoka¹  Takaharu Asano¹  Takehito Okui¹  Sasha A. Singh¹  Elena Aikawa²  Masanori Aikawa² 

[1] Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States;Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States;Center for Excellence in Vascular Biology, Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States;Department of Human Pathology, Sechenov First Moscow State Medical University, Moscow, Russia;

关键词: calcification;    drug discovery;    drug repurposing;    Wnt signaling;    mouse models;    proteomics;   

DOI  :  10.3389/fcvm.2021.826529

 received in 2021-11-30, accepted in 2021-12-27,  发布年份 2022

来源: Frontiers

【 摘 要 】

Vascular calcification is a cardiovascular disorder with no therapeutic options. We recently reported that o-octanoyltransferase (CROT) suppression can inhibit vascular calcification in vivo and in vitro through amelioration of mitochondrial function and fatty acid metabolism. Inhibiting calcification with a small molecule compound targeting CROT-associated mechanisms will be a promising non-invasive treatment of vascular calcification. Here we used a computational approach to search for existing drugs that can inhibit vascular calcification through the CROT pathway. For screening of the compounds that reduce CROT expression, we utilized the Connectivity Map encompassing the L1000 computational platform that contains transcription profiles of various cell lines and perturbagens including small molecules. Small molecules (n = 13) were identified and tested in human primary smooth muscle cells cultured in osteogenic media to induce calcification. Niclosamide, an FDA-improved anthelmintic drug, markedly inhibited calcification along with reduced alkaline phosphatase activity and CROT mRNA expression. To validate this compound in vivo, LDL receptor (Ldlr)-deficient mice fed a high fat diet were given oral doses of niclosamide (0 or 750 ppm admixed with diet) for 10 weeks. Niclosamide treatment decreased aortic and carotid artery calcification as determined by optical near infrared molecular imaging (OsteoSense680) and histological analysis. In addition, niclosamide improved features of fatty liver, including decreased cholesterol levels along with decreased Crot expression, while plasma total cholesterol levels did not change. Proteomic analysis of aortic samples demonstrated that niclosamide affected wingless/integrated (Wnt) signaling pathway and decreased runt-related transcription factor 2 (Runx2) expression, an essential factor for calcification. Our target discovery strategy using a genetic perturbation database with existing drugs identified niclosamide, that in turn inhibited calcification in vivo and in vitro, indicating its potential for the treatment of vascular calcification.

【 授权许可】

Unknown   
Copyright © 2022 Tanaka, Asano, Okui, Kuraoka, Singh, Aikawa and Aikawa.