TY - JOUR
T1 - Methylene blue is a potent and broad-spectrum inhibitor against Zika virus in vitro and in vivo
AU - Li, Zhong
AU - Lang, Yuekun
AU - Sakamuru, Srilatha
AU - Samrat, Subodh
AU - Trudeau, Nicole
AU - Kuo, Lili
AU - Rugenstein, Natasha
AU - Tharappel, Anil
AU - D'Brant, Lianna
AU - Koetzner, Cheri A.
AU - Hu, Saiyang
AU - Zhang, Jing
AU - Huang, Ruili
AU - Kramer, Laura D.
AU - Butler, David
AU - Xia, Menghang
AU - Li, Hongmin
N1 - Funding Information:
This work was partially supported by the Wadsworth Center flavivirus drug discovery seed funding, by NIH grants AI131669, AI133219, Ai134568, and AI140491 to H.L. (National Institute of Allergy and Infectious Diseases), and by the Intramural Research Program of NCATS, NIH (M.X.) (National Center for Advancing Translational Sciences). We thank Dr. Radhakrishnan Padmanabhan at Georgetown University for the gift of the DENV2 replicon BHK-21 cell line and Dr. Cara Pager at University at Albany for the gift Zika virus strain FSS13025. We also thank the Wadsworth Center Tissue Culture Core facility for help with cell culture and media preparation, the Advanced Light Microscopy Core for immunofluorescence/confocal imaging, animal facility for animal care, and Dr. Kimberly McClive-Reed of Health Research, Inc. for helpful suggestions. The following reagents were obtained through BEI Resources, NIAID, NIH as part of the Human Microbiome Project: Zika virus strains MR766, MEX I-44, and BeH819015.
Publisher Copyright:
© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Many flaviviruses including the Dengue virus (DENV), Zika virus (ZIKV), West Nile virus, Yellow Fever virus, and Japanese encephalitis virus are significant human pathogens, unfortunately without any specific therapy. Here, we demonstrate that methylene blue, an FDA-approved drug, is a broad-spectrum and potent antiviral against Zika virus and Dengue virus both in vitro and in vivo. We found that methylene blue can considerably inhibit the interactions between viral protease NS3 and its NS2B co-factor, inhibit viral protease activity, inhibit viral growth, protect 3D mini-brain organoids from ZIKV infection, and reduce viremia in a mouse model. Mechanistic studies confirmed that methylene blue works in both entry and post entry steps, reduces virus production in replicon cells and inhibited production of processed NS3 protein. Overall, we have shown that methylene blue is a potent antiviral for management of flavivirus infections, particularly for Zika virus. As an FDA-approved drug, methylene blue is well-tolerated for human use. Therefore, methylene blue represents a promising and easily developed therapy for management of infections by ZIKV and other flaviviruses.
AB - Many flaviviruses including the Dengue virus (DENV), Zika virus (ZIKV), West Nile virus, Yellow Fever virus, and Japanese encephalitis virus are significant human pathogens, unfortunately without any specific therapy. Here, we demonstrate that methylene blue, an FDA-approved drug, is a broad-spectrum and potent antiviral against Zika virus and Dengue virus both in vitro and in vivo. We found that methylene blue can considerably inhibit the interactions between viral protease NS3 and its NS2B co-factor, inhibit viral protease activity, inhibit viral growth, protect 3D mini-brain organoids from ZIKV infection, and reduce viremia in a mouse model. Mechanistic studies confirmed that methylene blue works in both entry and post entry steps, reduces virus production in replicon cells and inhibited production of processed NS3 protein. Overall, we have shown that methylene blue is a potent antiviral for management of flavivirus infections, particularly for Zika virus. As an FDA-approved drug, methylene blue is well-tolerated for human use. Therefore, methylene blue represents a promising and easily developed therapy for management of infections by ZIKV and other flaviviruses.
KW - antiviral
KW - Dengue virus
KW - flavivirus
KW - Methylene blue
KW - protease inhibitor
KW - Zika virus
UR - http://www.scopus.com/inward/record.url?scp=85095114174&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095114174&partnerID=8YFLogxK
U2 - 10.1080/22221751.2020.1838954
DO - 10.1080/22221751.2020.1838954
M3 - Article
C2 - 33078696
AN - SCOPUS:85095114174
VL - 9
SP - 2404
EP - 2416
JO - Emerging Microbes and Infections
JF - Emerging Microbes and Infections
SN - 2222-1751
IS - 1
ER -