Paving new roads toward the advancement of broad-spectrum antiviral agents.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 7705876 Publication Model: Print Cited Medium: Internet ISSN: 1096-9071 (Electronic) Linking ISSN: 01466615 NLM ISO Abbreviation: J Med Virol Subsets: MEDLINE

Publication: New York Ny : Wiley-Liss
Original Publication: New York, Liss.

Antiviral Agents*/pharmacology ; Virus Diseases*/drug therapy; Animals ; Humans ; Chiroptera/immunology ; Chiroptera/virology ; Homeostasis ; Medicine, Chinese Traditional ; Drug Development

Broad-spectrum antivirals (BSAs) have the advantageous property of being effective against a wide range of viruses with a single drug, offering a promising therapeutic solution for the largely unmet need in treating both existing and emerging viral infections. In this review, we summarize the current strategies for the development of novel BSAs, focusing on either targeting the commonalities during the replication of multiple viruses or the systemic immunity of humans. In comparison to BSAs that target viral replication, these immuno-modulatory agents possess an expanded spectrum of antiviral activity. However, antiviral immunity is a double-edged sword, and maintaining immune homeostasis ultimately dictates the health status of hosts during viral infections. Therefore, establishing an ideal goal for immuno-modulation in antiviral interventions is crucial. Herein we propose a bionic approach for immuno-modulation inspired by mimicking bats, which possess a more robust immune system for combating viral invasions, compared to humans. In addition, we discuss an empirical approach to treat diverse viral infections using traditional Chinese medicines (TCMs), mainly through bidirectional immuno-modulation to restore the disrupted homeostasis. Advancing our understanding of both the immune system of bats and the mechanisms underlying antiviral TCMs will significantly contribute to the future development of novel BSAs.
(© 2024 Wiley Periodicals LLC.)

Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-273.
Li M, Wang H, Tian L, et al. COVID-19 vaccine development: milestones, lessons and prospects. Signal Transduct Target Ther. 2022;7(1):146.
Li G, Hilgenfeld R, Whitley R, De Clercq E. Therapeutic strategies for COVID-19: progress and lessons learned. Nat Rev Drug Discovery. 2023;22(6):449-475.
WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int/. Accessed Aug 17, 2023.
Van Kerkhove MD, Ryan MJ, Ghebreyesus TA. Preparing for “disease X”. Science. 2021;374(6566):377.
Wouters OJ, McKee M, Luyten J. Estimated research and development investment needed to bring a new medicine to market, 2009-2018. JAMA. 2020;323(9):844-853.
Cui W, Aouidate A, Wang S, Yu Q, Li Y, Yuan S. Discovering anti-cancer drugs via computational methods. Front Pharmacol. 2020;11:733.
Mirza AZ, Shamshad H, Osra FA, Habeebullah TM, Morad M. An overview of viruses discovered over the last decades and drug development for the current pandemic. Eur J Pharmacol. 2021;890:173746.
Tompa DR, Immanuel A, Srikanth S, Kadhirvel S. Trends and strategies to combat viral infections: a review on FDA approved antiviral drugs. Int J Biiol Macromol. 2021;172:524-541.
Karim M, Lo CW, Einav S. Preparing for the next viral threat with broad-spectrum antivirals. J Clin Invest. 2023;133(11):e170236.
Vigant F, Santos NC, Lee B. Broad-spectrum antivirals against viral fusion. Nat Rev Microbiol. 2015;13(7):426-437.
Whitley R, Alford C, Hess F, Buchanan R. Vidarabine: a preliminary review of its pharmacological properties and therapeutic use. Drugs. 1980;20(4):267-282.
Geraghty R, Aliota M, Bonnac L. Broad-spectrum antiviral strategies and nucleoside analogues. Viruses. 2021;13(4):667.
Lu L, Su S, Yang H, Jiang S. Antivirals with common targets against highly pathogenic viruses. Cell. 2021;184(6):1604-1620.
Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531(7594):381-385.
Wang RR, Yang QH, Luo RH, et al. Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro. PLoS One. 2014;9(8):e105617.
Toots M, Yoon JJ, Hart M, Natchus MG, Painter GR, Plemper RK. Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model. Transl Res. 2020;218:16-28.
de Vries M, Mohamed AS, Prescott RA, et al. A comparative analysis of SARS-CoV-2 antivirals characterizes 3CL(pro) inhibitor PF-00835231 as a potential new treatment for COVID-19. J Virol. 2021;95(7):e01819-20.
Brai A, Fazi R, Tintori C, et al. Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents. Proc Natl Acad Sci USA. 2016;113(19):5388-5393.
Zheng Y, Li S, Song K, et al. A broad antiviral strategy: inhibitors of human DHODH pave the way for host-targeting antivirals against emerging and re-emerging viruses. Viruses. 2022;14(5):928.
Schor S, Einav S. Repurposing of kinase inhibitors as broad-spectrum antiviral drugs. DNA Cell Biol. 2018;37(2):63-69.
Stukalov A, Girault V, Grass V, et al. Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature. 2021;594(7862):246-252.
Gordon DE, Hiatt J, Bouhaddou M, et al. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science. 2020;370(6521):eabe9403.
Daniloski Z, Jordan TX, Wessels HH, et al. Identification of required host factors for SARS-CoV-2 infection in human cells. Cell. 2021;184(1):92-105.e16.
Olivet J, Maseko SB, Volkov AN, et al. A systematic approach to identify host targets and rapidly deliver broad-spectrum antivirals. Mol Ther. 2022;30(5):1797-1800.
Ji X, Li Z. Medicinal chemistry strategies toward host targeting antiviral agents. Med Res Rev. 2020;40(5):1519-1557.
Adalja A, Inglesby T. Broad-spectrum antiviral agents: a crucial pandemic tool. Expert Rev Anti Infect Ther. 2019;17(7):467-470.
Ezeonwumelu IJ, Garcia-Vidal E, Ballana E. JAK-STAT pathway: a novel target to tackle viral infections. Viruses. 2021;13(12):2379.
Maarifi G, Martin MF, Zebboudj A, et al. Identifying enhancers of innate immune signaling as broad-spectrum antivirals active against emerging viruses. Cell Chemical Biology. 2022;29(7):1113-1125.e6.
Pattabhi S, Wilkins CR, Dong R, et al. Targeting innate immunity for antiviral therapy through small molecule agonists of the RLR pathway. J Virol. 2016;90(5):2372-2387.
Smits SL, de Lang A, van den Brand JMA, et al. Exacerbated innate host response to SARS-CoV in aged non-human primates. PLoS Pathog. 2010;6(2):e1000756.
Stout-Delgado HW, Yang X, Walker WE, Tesar BM, Goldstein DR. Aging impairs IFN regulatory factor 7 up-regulation in plasmacytoid dendritic cells during TLR9 activation. J Immunol. 2008;181(10):6747-6756.
Lei X, Dong X, Ma R, et al. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat Commun. 2020;11(1):3810.
Miorin L, Kehrer T, Sanchez-Aparicio MT, et al. SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling. Proc Natl Acad Sci USA. 2020;117(45):28344-28354.
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
Sallard E, Lescure FX, Yazdanpanah Y, Mentre F, Peiffer-Smadja N. Type 1 interferons as a potential treatment against COVID-19. Antiviral Res. 2020;178:104791.
Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222.
Chan JFW, Yao Y, Yeung ML, et al. Treatment with lopinavir/ritonavir or Interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis. 2015;212(12):1904-1913.
Zeng YM, Xu XL, He XQ, et al. Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha, and ribavirin plus lopinavir/ritonavir plus interferon-alpha in patients with mild to moderate novel coronavirus disease 2019: study protocol. Chin Med J. 2020;133(9):1132-1134.
Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14(11):1090-1095.
Tam AR, Zhang RR, Lung KC, et al. Early treatment of high-risk hospitalized coronavirus disease 2019 (COVID-19) patients with a combination of interferon Beta-1b and remdesivir: a phase 2 open-label randomized controlled trial. Clin Infect Dis. 2023;76(3):e216-e226.
Channappanavar R, Fehr AR, Zheng J, et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest. 2019;129(9):3625-3639.
Kalil AC, Mehta AK, Patterson TF, et al. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Resp Med. 2021;9(12):1365-1376.
Jamilloux Y, Henry T, Belot A, et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev. 2020;19(7):102567.
Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17(4):233-247.
Matthay MA, Thompson BT. Dexamethasone in hospitalised patients with COVID-19: addressing uncertainties. Lancet Resp Med. 2020;8(12):1170-1172.
Leroy EM, Kumulungui B, Pourrut X, et al. Fruit bats as reservoirs of Ebola virus. Nature. 2005;438(7068):575-576.
Chua KB, Lek Koh C, Hooi PS, et al. Isolation of Nipah virus from Malaysian island flying-foxes. Microb Infect. 2002;4(2):145-151.
Li W, Shi Z, Yu M, et al. Bats are natural reservoirs of SARS-like coronaviruses. Science. 2005;310(5748):676-679.
Irving AT, Ahn M, Goh G, Anderson DE, Wang LF. Lessons from the host defences of bats, a unique viral reservoir. Nature. 2021;589(7842):363-370.
Zhou P, Tachedjian M, Wynne JW, et al. Contraction of the type I IFN locus and unusual constitutive expression of IFN-α in bats. Proc Natl Acad Sci USA. 2016;113(10):2696-2701.
Zhou P, Cowled C, Mansell A, et al. IRF7 in The Australian black flying fox, Pteropus alecto: evidence for a unique expression pattern and functional conservation. PLoS One. 2014;9(8):e103875.
Banerjee A, Zhang X, Yip A, et al. Positive selection of a serine residue in bat IRF3 confers enhanced antiviral protection. iScience. 2020;23(3):100958.
Banerjee A, Rapin N, Bollinger T, Misra V. Lack of inflammatory gene expression in bats: a unique role for a transcription repressor. Sci Rep. 2017;7(1):2232.
Ahn M, Anderson DE, Zhang Q, et al. Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host. Nat Microbiol. 2019;4(5):789-799.
Ahn M, Cui J, Irving AT, Wang LF. Unique loss of the PYHIN gene family in bats amongst mammals: implications for inflammasome sensing. Sci Rep. 2016;6:21722.
Xie J, Li Y, Shen X, et al. Dampened STING-Dependent interferon activation in bats. Cell Host Microbe. 2018;23(3):297-301.e4.
Host KM, Damania B. Discovery of a novel bat gammaherpesvirus. mSphere. 2016;1(1):e00016-16.
Subudhi S, Rapin N, Dorville N, et al. Isolation, characterization and prevalence of a novel gammaherpesvirus in Eptesicus fuscus, the North American big brown bat. Virology. 2018;516:227-238.
Mendenhall I, Wen D, Jayakumar J, et al. Diversity and evolution of viral pathogen community in cave nectar bats (Eonycteris spelaea). Viruses. 2019;11(3):250.
Drexler JF, Geipel A, König A, et al. Bats carry pathogenic hepadnaviruses antigenically related to hepatitis B virus and capable of infecting human hepatocytes. Proc Natl Acad Sci. 2013;110(40):16151-16156.
O'Dea MA, Tu SL, Pang S, De Ridder T, Jackson B, Upton C. Genomic characterization of a novel poxvirus from a flying fox: evidence for a new genus? J Gen Virol. 2016;97(9):2363-2375.
Misra V, Dumonceaux T, Dubois J, et al. Detection of polyoma and corona viruses in bats of Canada. J Gen Virol. 2009;90(Pt 8):2015-2022.
Fagrouch Z, Sarwari R, Lavergne A, et al. Novel polyomaviruses in south American bats and their relationship to other members of the family polyomaviridae. J Gen Virol. 2012;93(Pt 12):2652-2657.
Huang K, Zhang P, Zhang Z, et al. Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: efficacies and mechanisms. Pharmacol Ther. 2021;225:107843.
Ma Y, Zhou K, Fan J, Sun S. Traditional Chinese medicine: potential approaches from modern dynamical complexity theories. Front Med. 2016;10(1):28-32.
Li BH, Li ZY, Liu MM, Tian JZ, Cui QH. Progress in traditional Chinese medicine against respiratory viruses: a review. Front Pharmacol. 2021;12:743623.
Xu H, Li S, Liu J, et al. Bioactive compounds from Huashi Baidu decoction possess both antiviral and anti-inflammatory effects against COVID-19. Proc Natl Acad Sci USA. 2023;120(18):e2301775120.
Shi N, Liu B, Liang N, et al. Association between early treatment with Qingfei Paidu decoction and favorable clinical outcomes in patients with COVID-19: a retrospective multicenter cohort study. Pharmacol Res. 2020;161:105290.
Zhang L, Zheng X, Bai X, et al. Association between use of Qingfei Paidu Tang and mortality in hospitalized patients with COVID-19: a national retrospective registry study. Phytomedicine. 2021;85:153531.
Wang K, Yan H, Wu S, Wang H, Li Y, Jiang J. Inhibitory effect of Qing-Fei-Pai-Du decoction on coronavirus in vitro. Acta Pharm Sin. 2021;56(05):1400-1408.
Chen J, Wang Y, Gao Y, et al. Protection against COVID-19 injury by qingfei paidu decoction via anti-viral, anti-inflammatory activity and metabolic programming. Biomed Pharmacother. 2020;129:110281.
Ximeng LI, Yuan K, Wenjing LI, et al. Comparing the effects of three decoctions for coronavirus disease 2019 on severe acute respiratory syndrome coronavirus 2-related toll-like receptors-mediated inflammations. J Tradit Chin Med. 2023;43(1):51-59.
Li Y, Li B, Wang P, Wang Q. Traditional Chinese medicine, qingfei paidu decoction and Xuanfei Baidu decoction, inhibited cytokine production via NF-κB signaling pathway in macrophages: implications for coronavirus disease 2019 (COVID-19) therapy. Front Pharmacol. 2021;12:722126.
Niu W, Wu F, Cao W, et al. Network pharmacology for the identification of phytochemicals in traditional Chinese medicine for COVID-19 that may regulate interleukin-6. Biosci Rep. 2021;41(1):BSR20202583.
Ye XL, Tian SS, Tang CC, et al. Cytokine storm in acute viral respiratory injury: role of Qing-Fei-Pai-Du decoction in inhibiting the infiltration of neutrophils and macrophages through TAK1/IKK/NF-κB pathway. Am J Chin Med. 2023;51(5):1153-1188.
Zhang M, Zhong J, Xiong Y, Song X, Li C, He Z. Development of broad-spectrum antiviral agents-inspiration from immunomodulatory natural products. Viruses. 2021;13(7):1257.

82104134 National Natural Science Foundation of China; 2021GXRC028 Jinan Independent Training Innovative Team; 2022IOV003 Open Research Fund Program of the State Key Laboratory of Virology of China

Keywords: bat; broad-spectrum antiviral; immuno-modulation; traditional Chinese medicine

0 (Antiviral Agents)

Date Created: 20240105 Date Completed: 20240108 Latest Revision: 20240710

20240710

10.1002/jmv.29369

38180269