Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Zika Virus | Research article

Antiviral activity and mechanism of the antifungal drug, anidulafungin, suggesting its potential to promote treatment of viral diseases

Authors: Shu Shen, Yaxian Zhang, Zhiyun Yin, Qiong Zhu, Jingyuan Zhang, Tiantian Wang, Yaohui Fang, Xiaoli Wu, Yuan Bai, Shiyu Dai, Xijia Liu, Jiayin Jin, Shuang Tang, Jia Liu, Manli Wang, Yu Guo, Fei Deng

Published in: BMC Medicine | Issue 1/2022

Login to get access

Abstract

Background

The severe fever with thrombocytopenia syndrome disease (SFTS), caused by the novel tick-borne SFTS virus (SFTSV), was listed among the top 10 priority infectious disease by World Health Organization due to the high fatality rate of 5–30% and the lack of effective antiviral drugs and vaccines and therefore raised the urgent need to develop effective anti-SFTSV drugs to improve disease treatment.

Methods

The antiviral drugs to inhibit SFTSV infection were identified by screening the library containing 1340 FDA-approved drugs using the SFTSV infection assays in vitro. The inhibitory effect on virus entry and the process of clathrin-mediated endocytosis under different drug doses was evaluated based on infection assays by qRT-PCR to determine intracellular viral copies, by Western blot to characterize viral protein expression in cells, and by immunofluorescence assays (IFAs) to determine virus infection efficiencies. The therapeutic effect was investigated in type I interferon receptor defective A129 mice in vivo with SFTSV infection, from which lesions and infection in tissues caused by SFTSV infection were assessed by H&E staining and immunohistochemical analysis.

Results

Six drugs were identified as exerting inhibitory effects against SFTSV infection, of which anidulafungin, an antifungal drug of the echinocandin family, has a strong inhibitory effect on SFTSV entry. It suppresses SFTSV internalization by impairing the late endosome maturation and decreasing virus fusion with the membrane. SFTSV-infected A129 mice had relieving symptoms, reduced tissue lesions, and improved disease outcomes following anidulafungin treatment. Moreover, anidulafungin exerts an antiviral effect in inhibiting the entry of other viruses including SARS-CoV-2, SFTSV-related Guertu virus and Heartland virus, Crimean-Congo hemorrhagic fever virus, Zika virus, and Herpes simplex virus 1.

Conclusions

The results demonstrated that the antifungal drug, anidulafungin, could effectively inhibit virus infection by interfering with virus entry, suggesting it may be utilized for the clinical treatment of infectious viral diseases, in addition to its FDA-approved use as an antifungal. The findings also suggested to further evaluate the anti-viral effects of echinocandins and their clinical importance for patients with infection of viruses, which may promote therapeutic strategies as well as treatments and improve outcomes pertaining to various viral and fungal diseases.
Appendix
Available only for authorised users
Literature
1.
Yu XJ, Liang MF, Zhang SY, Liu Y, Li JD, Sun YL, et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med. 2011;364(16):1523–32.PubMedPubMedCentralCrossRef
2.
Kim KH, Yi J, Kim G, Choi SJ, Jun KI, Kim NH, et al. Severe fever with thrombocytopenia syndrome, South Korea, 2012. Emerg Infect Dis. 2013;19(11):1892–4.PubMedPubMedCentralCrossRef
3.
Kurihara S, Satoh A, Yu F, Hayasaka D, Shimojima M, Tashiro M, et al. The world first two cases of severe fever with thrombocytopenia syndrome: an epidemiological study in Nagasaki, Japan. J Infect Chemother. 2016;22(7):461–5.PubMedCrossRef
4.
Tran XC, Yun Y, Van An L, Kim SH, Thao NTP, Man PKC, et al. Endemic severe fever with thrombocytopenia syndrome, Vietnam. Emerg Infect Dis. 2019;25(5):1029–31.PubMedPubMedCentralCrossRef
5.
Xiong S, Zhang W, Li M, Xiong Y, Li M, Wang H, et al. A simple and practical score model for predicting the mortality of severe fever with thrombocytopenia syndrome patients. Medicine. 2016;95(52):e5708.PubMedPubMedCentralCrossRef
6.
Huang X, Li J, Li A, Wang S, Li D. Epidemiological characteristics of severe fever with thrombocytopenia syndrome from 2010 to 2019 in Mainland China. Int J Environ Res Public Health. 2021;18(6):3092.PubMedPubMedCentralCrossRef
7.
Luo LM, Zhao L, Wen HL, Zhang ZT, Liu JW, Fang LZ, et al. Haemaphysalis longicornis ticks as reservoir and vector of severe fever with thrombocytopenia syndrome virus in China. Emerg Infect Dis. 2015;21(10):1770–6.PubMedPubMedCentralCrossRef
8.
Chen H, Hu K, Zou J, Xiao J. A cluster of cases of human-to-human transmission caused by severe fever with thrombocytopenia syndrome bunyavirus. Int J Infect Dis. 2013;17(3):e206–8.PubMedCrossRef
9.
Tang X, Wu W, Wang H, Du Y, Liu L, Kang K, et al. Human-to-human transmission of severe fever with thrombocytopenia syndrome bunyavirus through contact with infectious blood. J Infect Dis. 2013;207(5):736–9.PubMedCrossRef
10.
Shimojima M, Fukushi S, Tani H, Yoshikawa T, Fukuma A, Taniguchi S, et al. Effects of ribavirin on severe fever with thrombocytopenia syndrome virus in vitro. Jpn J Infect Dis. 2014;67(6):423–7.PubMedCrossRef
11.
Lu Q, Zhang S, Cui N, Hu J, Fan Y, Guo C, et al. Common adverse events associated with ribavirin therapy for severe fever with thrombocytopenia syndrome. Antiviral Res. 2015;119:19–22.PubMedCrossRef
12.
Wu Y, Zhu Y, Gao F, Jiao Y, Oladejo BO, Chai Y, et al. Structures of phlebovirus glycoprotein Gn and identification of a neutralizing antibody epitope. Proc Natl Acad Sci U S A. 2017;114(36):E7564–73.PubMedPubMedCentralCrossRef
13.
Liu J, Xu M, Tang B, Hu L, Deng F, Wang H, et al. Single-particle tracking reveals the sequential entry process of the Bunyavirus severe fever with thrombocytopenia syndrome virus. Small. 2019;15(6):e1803788.PubMedCrossRef
14.
Vogel D, Thorkelsson SR, Quemin ERJ, Meier K, Kouba T, Gogrefe N, et al. Structural and functional characterization of the severe fever with thrombocytopenia syndrome virus L protein. Nucleic acids Res. 2020;48(10):5749–65.PubMedPubMedCentralCrossRef
15.
Spiegel M, Plegge T, Pohlmann S. The role of Phlebovirus glycoproteins in viral entry, assembly and release. Viruses. 2016;8(7):202.PubMedCentralCrossRef
16.
Lam TT, Liu W, Bowden TA, Cui N, Zhuang L, Liu K, et al. Evolutionary and molecular analysis of the emergent severe fever with thrombocytopenia syndrome virus. Epidemics. 2013;5(1):1–10.PubMedPubMedCentralCrossRef
17.
Shen S, Duan X, Wang B, Zhu L, Zhang Y, Zhang J, et al. A novel tick-borne phlebovirus, closely related to severe fever with thrombocytopenia syndrome virus and Heartland virus, is a potential pathogen. Emerg Microbes Infect. 2018;7(1):95.PubMedPubMedCentralCrossRef
18.
Guo R, Shen S, Zhang Y, Shi J, Su Z, Liu D, et al. A new strain of Crimean-Congo hemorrhagic fever virus isolated from Xinjiang, China. Virol Sin. 2017;32(1):80–8.PubMedPubMedCentralCrossRef
19.
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–3.PubMedPubMedCentralCrossRef
20.
Huang D, Jiang Y, Liu X, Wang B, Shi J, Su Z, et al. A cluster of symptomatic and asymptomatic infections of severe fever with thrombocytopenia syndrome caused by person-to-person transmission. Am J Trop Med Hyg. 2017;97(2):396–402.PubMedPubMedCentralCrossRef
21.
Ning YJ, Wang M, Deng M, Shen S, Liu W, Cao WC, et al. Viral suppression of innate immunity via spatial isolation of TBK1/IKKepsilon from mitochondrial antiviral platform. J Mol Cell Biol. 2014;6(4):324–37.PubMedCrossRef
22.
Feng K, Deng F, Hu Z, Wang H, Ning YJ. Heartland virus antagonizes type I and III interferon antiviral signaling by inhibiting phosphorylation and nuclear translocation of STAT2 and STAT1. J Biol Chem. 2019;294(24):9503–17.PubMedPubMedCentralCrossRef
23.
Guo Y, Huang L, Zhang G, Yao Y, Zhou H, Shen S, et al. A SARS-CoV-2 neutralizing antibody with extensive Spike binding coverage and modified for optimal therapeutic outcomes. Nat Commun. 2021;12(1):2623.PubMedPubMedCentralCrossRef
24.
Du R, Wang L, Xu H, Wang Z, Zhang T, Wang M, et al. A novel glycoprotein D-specific monoclonal antibody neutralizes herpes simplex virus. Antiviral Res. 2017;147:131–41.PubMedPubMedCentralCrossRef
25.
Li H, Zhang LK, Li SF, Zhang SF, Wan WW, Zhang YL, et al. Calcium channel blockers reduce severe fever with thrombocytopenia syndrome virus (SFTSV) related fatality. Cell Res. 2019;29(9):739–53.PubMedPubMedCentralCrossRef
26.
Zhang Y, Shen S, Shi J, Su Z, Li M, Zhang W, et al. Isolation, characterization, and phylogenic analysis of three new severe fever with thrombocytopenia syndrome bunyavirus strains derived from Hubei Province, China. Virol Sin. 2017;32(1):89–96.PubMedPubMedCentralCrossRef
27.
Zhang JH, Chung TD, Oldenburg KR. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen. 1999;4(2):67–73.PubMedCrossRef
28.
Wan W, Zhu S, Li S, Shang W, Zhang R, Li H, et al. High-throughput screening of an FDA-approved drug library identifies inhibitors against Arenaviruses and SARS-CoV-2. ACS Infect Dis. 2021;7(6):1409–22.PubMedCrossRef
29.
Zhu L, Yin F, Moming A, Zhang J, Wang B, Gao L, et al. First case of laboratory-confirmed severe fever with thrombocytopenia syndrome disease revealed the risk of SFTSV infection in Xinjiang, China. Emerg Microbes Infect. 2019;8(1):1122–5.PubMedPubMedCentralCrossRef
30.
Zhang LK, Wang B, Xin Q, Shang W, Shen S, Xiao G, et al. Quantitative proteomic analysis reveals unfolded-protein response involved in severe fever with thrombocytopenia syndrome virus infection. J Virol. 2019;93(10):e00308–19.PubMedPubMedCentralCrossRef
31.
Hu L, Li Y, Ning YJ, Deng F, Vlak JM, Hu Z, et al. The major hurdle for effective Baculovirus transduction into mammalian cells is passing early endosomes. J Virol. 2019;93(15):e00709–19.PubMedPubMedCentralCrossRef
32.
Diwu Z, Chen CS, Zhang C, Klaubert DH, Haugland RP. A novel acidotropic pH indicator and its potential application in labeling acidic organelles of live cells. Chem Biol. 1999;6(7):411–8.PubMedCrossRef
33.
Stauffer S, Feng Y, Nebioglu F, Heilig R, Picotti P, Helenius A. Stepwise priming by acidic pH and a high K+ concentration is required for efficient uncoating of influenza A virus cores after penetration. J Virol. 2014;88(22):13029–46.PubMedPubMedCentralCrossRef
34.
Percie du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, et al. Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 2020;18(7):e3000411.PubMedPubMedCentralCrossRef
35.
Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 2020;18(7):e3000410.PubMedPubMedCentralCrossRef
36.
37.
Delang L, Abdelnabi R, Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res. 2018;153:85–94.PubMedCrossRef
38.
Tani H, Fukuma A, Fukushi S, Taniguchi S, Yoshikawa T, Iwata-Yoshikawa N, et al. Efficacy of T-705 (Favipiravir) in the treatment of infections with lethal severe fever with thrombocytopenia syndrome virus. mSphere. 2016;1(1):e00061–15.PubMedPubMedCentralCrossRef
39.
Li H, Jiang XM, Cui N, Yuan C, Zhang SF, Lu QB, et al. Clinical effect and antiviral mechanism of T-705 in treating severe fever with thrombocytopenia syndrome. Signal Transduct Target Ther. 2021;6(1):145.PubMedPubMedCentralCrossRef
40.
Yuan S, Chan JF, Ye ZW, Wen L, Tsang TG, Cao J, et al. Screening of an FDA-approved drug library with a two-tier system identifies an entry inhibitor of severe fever with thrombocytopenia syndrome virus. Viruses. 2019;11(4):385.PubMedCentralCrossRef
41.
42.
Houst J, Spizek J, Havlicek V. Antifungal drugs. Metabolites. 2020;10(3):106.CrossRef
43.
Koch J, Xin QL, Tischler ND, Lozach PY. Entry of Phenuiviruses into mammalian host cells. Viruses-Basel. 2021;13(2):299.CrossRef
44.
45.
Garrison AR, Radoshitzky SR, Kota KP, Pegoraro G, Ruthel G, Kuhn JH, et al. Crimean-Congo hemorrhagic fever virus utilizes a clathrin- and early endosome-dependent entry pathway. Virology. 2013;444(1-2):45–54.PubMedCrossRef
46.
Madavaraju K, Koganti R, Volety I, Yadavalli T, Shukla D. Herpes simplex virus cell entry mechanisms: an update. Front Cell Infect Microbiol. 2020;10:617578.PubMedCrossRef
47.
48.
49.
Ahamad S, Ali H, Secco I, Giacca M, Gupta D. Anti-fungal drug anidulafungin inhibits SARS-CoV-2 spike-induced syncytia formation by targeting ACE2-spike protein interaction. Front Genet. 2022;13:866474.PubMedPubMedCentralCrossRef
50.
51.
52.
Ho YJ, Liu FC, Yeh CT, Yang CM, Lin CC, Lin TY, et al. Micafungin is a novel anti-viral agent of chikungunya virus through multiple mechanisms. Antiviral Res. 2018;159:134–42.PubMedCrossRef
53.
Chen YC, Lu JW, Yeh CT, Lin TY, Liu FC, Ho YJ. Micafungin inhibits dengue virus infection through the disruption of virus binding, entry, and stability. Pharmaceuticals (Basel). 2021;14(4):338.PubMedPubMedCentralCrossRef
54.
Vergoten G, Bailly C. In silico analysis of echinocandins binding to the main proteases of coronaviruses PEDV (3CL(pro)) and SARS-CoV-2 (M (pro)). In Silico Pharmacol. 2021;9(1):41.PubMedPubMedCentralCrossRef
55.
Wang YC, Yang WH, Yang CS, Hou MH, Tsai CL, Chou YZ, et al. Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug. Am J Cancer Res. 2020;10(8):2535–45.PubMedPubMedCentral
56.
Marak BN, Dowarah J, Khiangte L, Singh VP. Step toward repurposing drug discovery for COVID-19 therapeutics through in silico approach. Drug Dev Res. 2021;82(3):374–92.PubMedCrossRef
57.
Schloer S, Brunotte L, Mecate-Zambrano A, Zheng S, Tang J, Ludwig S, et al. Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro. Br J Pharmacol. 2021;178(11):2339–50.PubMedCrossRef
58.
Van Damme E, De Meyer S, Bojkova D, Ciesek S, Cinatl J, De Jonghe S, et al. In vitro activity of itraconazole against SARS-CoV-2. J Med Virol. 2021;93(7):4454–60.PubMedPubMedCentralCrossRef
59.
Schloer S, Goretzko J, Kuhnl A, Brunotte L, Ludwig S, Rescher U. The clinically licensed antifungal drug itraconazole inhibits influenza virus in vitro and in vivo. Emerg Microbes Infect. 2019;8(1):80–93.PubMedPubMedCentralCrossRef
60.
Kummer S, Lander A, Goretzko J, Kirchoff N, Rescher U, Schloer S. Pharmacologically induced endolysosomal cholesterol imbalance through clinically licensed drugs itraconazole and fluoxetine impairs Ebola virus infection in vitro. Emerg Microbes Infect. 2022;11(1):195–207.PubMedPubMedCentralCrossRef
61.
Rhoden E, Nix WA, Weldon WC, Selvarangan R. Antifungal azoles itraconazole and posaconazole exhibit potent in vitro antiviral activity against clinical isolates of parechovirus A3 (Picornaviridae). Antiviral Res. 2018;149:75–7.PubMedCrossRef
62.
Sari AP, Darnindro N, Yohanes A, Mokoagow MI. Role of tocilizumab for concomitant systemic fungal infection in severe COVID-19 patient: case report. Medicine. 2021;100(12):e25173.PubMedPubMedCentralCrossRef
63.
Salehi M, Ahmadikia K, Mahmoudi S, Kalantari S, Jamalimoghadamsiahkali S, Izadi A, et al. Oropharyngeal candidiasis in hospitalised COVID-19 patients from Iran: species identification and antifungal susceptibility pattern. Mycoses. 2020;63(8):771–8.PubMedPubMedCentralCrossRef
Metadata
Title
Antiviral activity and mechanism of the antifungal drug, anidulafungin, suggesting its potential to promote treatment of viral diseases
Authors
Shu Shen
Yaxian Zhang
Zhiyun Yin
Qiong Zhu
Jingyuan Zhang
Tiantian Wang
Yaohui Fang
Xiaoli Wu
Yuan Bai
Shiyu Dai
Xijia Liu
Jiayin Jin
Shuang Tang
Jia Liu
Manli Wang
Yu Guo
Fei Deng
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02558-z

Other articles of this Issue 1/2022

BMC Medicine 1/2022 Go to the issue

Research article

Biological aging mediates the associations between urinary metals and osteoarthritis among U.S. adults

Research article

Describing the population experiencing COVID-19 vaccine breakthrough following second vaccination in England: a cohort study from OpenSAFELY

Research article

The empirical support for the radical cure strategy for eliminating Plasmodium vivax in China

Review

Obese visceral fat tissue inflammation: from protective to detrimental?

Research article

A retrospective database study of the demographic features and glycemic control of patients with type 2 diabetes in Kinshasa, Democratic Republic of the Congo

Research article

Association between adverse childhood experiences and premenstrual disorders: a cross-sectional analysis of 11,973 women