Frontiers in Immunology (Dec 2022)
Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model
- Yun-Ti Chen,
- Yu-Hsiu Chang,
- Yu-Hsiu Chang,
- Nikhil Pathak,
- Shey-Cherng Tzou,
- Shey-Cherng Tzou,
- Shey-Cherng Tzou,
- Yong-Chun Luo,
- Yen-Chao Hsu,
- Tian-Neng Li,
- Jung-Yu Lee,
- Yi-Cyun Chen,
- Yu-Wei Huang,
- Hsin-Ju Yang,
- Nung-Yu Hsu,
- Hui-Ping Tsai,
- Tein-Yao Chang,
- Tein-Yao Chang,
- Shu-Chen Hsu,
- Ping-Cheng Liu,
- Yuan-Fan Chin,
- Wen-Chin Lin,
- Chuen-Mi Yang,
- Hsueh-Ling Wu,
- Chia-Ying Lee,
- Hui-Ling Hsu,
- Hui-Ling Hsu,
- Yi-Chun Liu,
- Jhih-Wei Chu,
- Jhih-Wei Chu,
- Lily Hui-Ching Wang,
- Jann-Yuan Wang,
- Chih-Heng Huang,
- Chih-Heng Huang,
- Chih-Heng Huang,
- Chi-Hung Lin,
- Chi-Hung Lin,
- Chi-Hung Lin,
- Po-Shiuan Hsieh,
- Yan-Hwa Wu Lee,
- Yan-Hwa Wu Lee,
- Yi-Jen Hung,
- Yi-Jen Hung,
- Jinn-Moon Yang,
- Jinn-Moon Yang,
- Jinn-Moon Yang
Affiliations
- Yun-Ti Chen
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Yu-Hsiu Chang
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Yu-Hsiu Chang
- Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
- Nikhil Pathak
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Shey-Cherng Tzou
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Shey-Cherng Tzou
- Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Shey-Cherng Tzou
- Center for Intelligent Drug Systems and Smart Bio-Devices, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Yong-Chun Luo
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Yen-Chao Hsu
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Tian-Neng Li
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
- Jung-Yu Lee
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Yi-Cyun Chen
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Yu-Wei Huang
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Hsin-Ju Yang
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Nung-Yu Hsu
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Hui-Ping Tsai
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Tein-Yao Chang
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Tein-Yao Chang
- Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
- Shu-Chen Hsu
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Ping-Cheng Liu
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Yuan-Fan Chin
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Wen-Chin Lin
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Chuen-Mi Yang
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Hsueh-Ling Wu
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Chia-Ying Lee
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Hui-Ling Hsu
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Hui-Ling Hsu
- Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
- Yi-Chun Liu
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Jhih-Wei Chu
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Jhih-Wei Chu
- Center for Intelligent Drug Systems and Smart Bio-Devices, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Lily Hui-Ching Wang
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
- Jann-Yuan Wang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Chih-Heng Huang
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Chih-Heng Huang
- Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
- Chih-Heng Huang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
- Chi-Hung Lin
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Chi-Hung Lin
- 0Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Chi-Hung Lin
- 1Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Po-Shiuan Hsieh
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
- Yan-Hwa Wu Lee
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Yan-Hwa Wu Lee
- Center for Intelligent Drug Systems and Smart Bio-Devices, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Yi-Jen Hung
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan
- Yi-Jen Hung
- 2Division of Endocrine and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Jinn-Moon Yang
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Jinn-Moon Yang
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Jinn-Moon Yang
- Center for Intelligent Drug Systems and Smart Bio-Devices, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- DOI
- https://doi.org/10.3389/fimmu.2022.1080897
- Journal volume & issue
-
Vol. 13
Abstract
BackgroundDrug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease.MethodsHere, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC50 = 0.4 μM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms.ResultsOur in vitro studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals.ConclusionsWe demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.
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