Your browser doesn't support javascript.
Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model.
Chen, Yun-Ti; Chang, Yu-Hsiu; Pathak, Nikhil; Tzou, Shey-Cherng; Luo, Yong-Chun; Hsu, Yen-Chao; Li, Tian-Neng; Lee, Jung-Yu; Chen, Yi-Cyun; Huang, Yu-Wei; Yang, Hsin-Ju; Hsu, Nung-Yu; Tsai, Hui-Ping; Chang, Tein-Yao; Hsu, Shu-Chen; Liu, Ping-Cheng; Chin, Yuan-Fan; Lin, Wen-Chin; Yang, Chuen-Mi; Wu, Hsueh-Ling; Lee, Chia-Ying; Hsu, Hui-Ling; Liu, Yi-Chun; Chu, Jhih-Wei; Wang, Lily Hui-Ching; Wang, Jann-Yuan; Huang, Chih-Heng; Lin, Chi-Hung; Hsieh, Po-Shiuan; Wu Lee, Yan-Hwa; Hung, Yi-Jen; Yang, Jinn-Moon.
  • Chen YT; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Chang YH; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Pathak N; Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.
  • Tzou SC; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Luo YC; Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Hsu YC; Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Li TN; Center for Intelligent Drug Systems and Smart Bio-Devices, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Lee JY; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Chen YC; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Huang YW; Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
  • Yang HJ; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Hsu NY; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Tsai HP; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Chang TY; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Hsu SC; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Liu PC; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Chin YF; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Lin WC; Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.
  • Yang CM; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Wu HL; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Lee CY; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Hsu HL; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Liu YC; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Chu JW; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Wang LH; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Wang JY; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Huang CH; Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.
  • Lin CH; Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
  • Hsieh PS; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Wu Lee YH; Center for Intelligent Drug Systems and Smart Bio-Devices, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
  • Hung YJ; Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
  • Yang JM; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Front Immunol ; 13: 1080897, 2022.
Article in English | MEDLINE | ID: covidwho-2198919
ABSTRACT

Background:

Drug 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.

Methods:

Here, 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.

Results:

Our 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.

Conclusions:

We 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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Experimental Studies / Prognostic study / Systematic review/Meta Analysis Topics: Variants Limits: Animals Language: English Journal: Front Immunol Year: 2022 Document Type: Article Affiliation country: Fimmu.2022.1080897

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Experimental Studies / Prognostic study / Systematic review/Meta Analysis Topics: Variants Limits: Animals Language: English Journal: Front Immunol Year: 2022 Document Type: Article Affiliation country: Fimmu.2022.1080897