Hesperetin blocks poxvirus replication with a low tendency to select for drug-resistant viral variants.
BPXV
buffalopox virus
eIF4E
hesperetin
m7GTP
poxvirus
Journal
Journal of medical virology
ISSN: 1096-9071
Titre abrégé: J Med Virol
Pays: United States
ID NLM: 7705876
Informations de publication
Date de publication:
Apr 2024
Apr 2024
Historique:
revised:
08
03
2024
received:
21
09
2023
accepted:
11
03
2024
medline:
28
3
2024
pubmed:
28
3
2024
entrez:
28
3
2024
Statut:
ppublish
Résumé
In this study, we demonstrated the antiviral efficacy of hesperetin against multiple poxviruses, including buffalopox virus (BPXV), vaccinia virus (VACV), and lumpy skin disease virus (LSDV). The time-of-addition and virus step-specific assays indicated that hesperetin reduces the levels of viral DNA, mRNA, and proteins in the target cells. Further, by immunoprecipitation (IP) of the viral RNA from BPXV-infected Vero cells and a cell-free RNA-IP assay, we demonstrated that hesperetin-induced reduction in BPXV protein synthesis is also consistent with diminished interaction between eukaryotic translation initiation factor eIF4E and the 5' cap of viral mRNA. Molecular docking and MD simulation studies were also consistent with the binding of hesperetin to the cap-binding pocket of eIF4E, adopting a conformation similar to m7GTP binding. Furthermore, in a BPXV egg infection model, hesperetin was shown to suppress the development of pock lesions on the chorioallantoic membrane and associated mortality in the chicken embryos. Most importantly, long-term culture of BPXV in the presence of hesperetin did not induce the generation of drug-resistant viral mutants. In conclusion, we, for the first time, demonstrated the antiviral activity of hesperetin against multiple poxviruses, besides providing some insights into its potential mechanisms of action.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e29555Subventions
Organisme : Science and Engineering Research Board
ID : CRG/2018/004747
Organisme : Science and Engineering Research Board
ID : CRG/2019/000829
Organisme : National Agricultural Science Funds, Govt of India
ID : NASF/ABA-8027/2020-21
Informations de copyright
© 2024 Wiley Periodicals LLC.
Références
Pan D, Nazareth J, Sze S, et al. Transmission of monkeypox/mpox virus: a narrative review of environmental, viral, host, and population factors in relation to the 2022 international outbreak. J Med Virol. 2023;95(2):e28534.
Kumar N, Tripathi BN. A serious skin virus epidemic sweeping through the Indian subcontinent is a threat to the livelihood of farmers. Virulence. 2022;13(1):1943‐1944.
Pandita S, Verma A, Kamboj H, et al. miRNA profiling of primary lamb testicle cells infected with lumpy skin disease virus. Arch Virol. 2023;168(12):290.
Kumar R, Chander Y, Verma A, Tripathi BN, Barua S, Kumar N. A novel HRM‐based gap‐qRT‐PCR for identification and quantitation of the vaccine and field strain(s) of lumpy skin disease virus. J Immunol Methods. 2023;519:113521.
Kumar R, Godara B, Chander Y, et al. Evidence of lumpy skin disease virus infection in camels. Acta Trop. 2023;242:106922.
Kumar N, Barua S, Kumar R, et al. Evaluation of the safety, immunogenicity and efficacy of a new live‐attenuated lumpy skin disease vaccine in India. Virulence. 2023;14(1):2190647.
Kumar N, Chander Y, Kumar R, et al. Isolation and characterization of lumpy skin disease virus from cattle in India. PLoS One. 2021;16(1):e0241022.
Haller SL, Peng C, McFadden G, Rothenburg S. Poxviruses and the evolution of host range and virulence. Infect Genet Evol. 2014;21:15‐40.
Bera BC, Shanmugasundaram K, Barua S, et al. Zoonotic cases of camelpox infection in India. Vet Microbiol. 2011;152(1‐2):29‐38.
Marinaik CB, Venkatesha MD, Gomes AR, Reddy P, Nandini P, Byregowda SM. Isolation and molecular characterization of zoonotic Buffalopox virus from skin lesions of humans in India. Int J Dermatol. 2018;57(5):590‐592.
Patil DY, George S, Sahay RR, et al. A case of human buffalopox in Malappuram, India: the role of mpox surveillance in 2022. J Med Virol. 2023;95(2):e28580.
Alakunle EF, Okeke MI. Monkeypox virus: a neglected zoonotic pathogen spreads globally. Nat Rev Microbiol. 2022;20(9):507‐508.
Caillat C, Topalis D, Agrofoglio LA, et al. Crystal structure of poxvirus thymidylate kinase: an unexpected dimerization has implications for antiviral therapy. Proc Natl Acad Sci. 2008;105(44):16900‐16905.
Yang H, Kim SK, Kim M, et al. Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction. J Clin Invest. 2005;115(2):379‐387.
Junge RE, Duncan MC, Miller RE, Gregg D, Kombert M. Clinical presentation and antiviral therapy for poxvirus infection in pudu (Pudu puda). J Zoo Wildl Med. 2000;31(3):412‐418.
De Clercq E. Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infections. Clin Microbiol Rev. 2001;14(2):382‐397.
Neyts J, De Clercq E. Efficacy of 2‐amino‐7‐(1,3‐dihydroxy‐2‐propoxymethyl)purine for treatment of vaccinia virus (orthopoxvirus) infections in mice. Antimicrob Agents Chemother. 2001;45(1):84‐87.
Snoeck R, De Clercq E. Role of cidofovir in the treatment of DNA virus infections, other than CMV infections, in immunocompromised patients. Curr Opin Investig Drugs. 2002;3(11):1561‐1566.
Grosenbach DW, Honeychurch K, Rose EA, et al. Oral tecovirimat for the treatment of smallpox. N Engl J Med. 2018;379(1):44‐53.
Broekema FI, Dikkers FG. Side‐effects of cidofovir in the treatment of recurrent respiratory papillomatosis. Eur Arch Otrhinolaryngol. 2008;265(8):871‐879.
Romanowski EG, Gordon YJ, Araullo‐Cruz T, Yates KA, Kinchington PR. The antiviral resistance and replication of cidofovir‐resistant adenovirus variants in the New Zealand White rabbit ocular model. Invest Ophthalmol Vis Sci. 2001;42(8):1812‐1815.
Chen F, Chu C, Wang X, et al. Hesperetin attenuates sepsis‐induced intestinal barrier injury by regulating neutrophil extracellular trap formation via the ROS/autophagy signaling pathway. Food Funct. 2023;14(9):4213‐4227.
Zaafar D, Khalil HMA, Rasheed RA, Eltelbany RFA, Zaitone SA. Hesperetin mitigates sorafenib‐induced cardiotoxicity in mice through inhibition of the TLR4/NLRP3 signaling pathway. PLoS One. 2022;17(8):e0271631.
Kong LN, Lin X, Huang C, et al. Hesperetin derivative‐12 (HDND‐12) regulates macrophage polarization by modulating JAK2/STAT3 signaling pathway. Chin J Nat Med. 2019;17(2):122‐130.
Cheng F‐J, Huynh T‐K, Yang C‐S, et al. Hesperidin is a potential inhibitor against SARS‐CoV‐2 infection. Nutrients. 2021;13(8):2800.
Zalpoor H, Bakhtiyari M, Shapourian H, Rostampour P, Tavakol C, Nabi‐Afjadi M. Hesperetin as an anti‐SARS‐CoV‐2 agent can inhibit COVID‐19‐associated cancer progression by suppressing intracellular signaling pathways. Inflammopharmacology. 2022;30(5):1533‐1539.
Sá JM, Piloto JV, Cilli EM, et al. Hesperetin targets the hydrophobic pocket of the nucleoprotein/phosphoprotein binding site of human respiratory syncytial virus. J Biomol Struct Dyn. 2022;40(5):2156‐2168.
Fatriansyah JF, Rizqillah RK, Yandi MY. Molecular docking and molecular dynamics simulation of fisetin, galangin, hesperetin, hesperidin, myricetin, and naringenin against polymerase of dengue virus. J Trop Med. 2022;2022:7254990.
Eberle RJ, Olivier DS, Pacca CC, et al. In vitro study of hesperetin and hesperidin as inhibitors of zika and chikungunya virus proteases. PLoS One. 2021;16(3):e0246319.
Paredes A, Alzuru M, Mendez J, Rodríguez‐Ortega M. Anti‐Sindbis activity of flavanones hesperetin and naringenin. Biol Pharm Bull. 2003;26(1):108‐109.
Kaul TN, Middleton Jr. E, Ogra PL. Antiviral effect of flavonoids on human viruses. J Med Virol. 1985;15(1):71‐79.
Kim H, Jeon W, Ko B. Flavanone glycosides from Citrus junos and their anti‐influenza virus activity. Planta Med. 2001;67(06):548‐549.
Khandelwal N, Chander Y, Kumar R, et al. Antiviral activity of Apigenin against buffalopox: novel mechanistic insights and drug‐resistance considerations. Antiviral Res. 2020;181:104870.
Schmidt FI, Bleck CKE, Helenius A, Mercer J. Vaccinia extracellular virions enter cells by macropinocytosis and acid‐activated membrane rupture. EMBO J. 2011;30(17):3647‐3661.
Mercer J, Knébel S, Schmidt FI, Crouse J, Burkard C, Helenius A. Vaccinia virus strains use distinct forms of macropinocytosis for host‐cell entry. Proce Natl Acad Sci. 2010;107(20):9346‐9351.
Chander Y, Kumar R, Verma A, et al Resistance evolution against host‐directed antiviral agents: buffalopox virus switches to use p38‐Upsilon under long‐term selective pressure of an inhibitor targeting p38‐alpha. Mol Biol Evol. 2022;39(9):msac177.
Khandelwal N, Chander Y, Rawat KD, et al. Emetine inhibits replication of RNA and DNA viruses without generating drug‐resistant virus variants. Antiviral Res. 2017;144:196‐204.
Rao X, Huang X, Zhou Z, Lin X. An improvement of the 2ˆ(‐delta delta CT) method for quantitative real‐time polymerase chain reaction data analysis. Biostat Bioinformatics Biomath. 2013;3(3):71‐85.
Chander Y, Kumar R, Verma A, et al. Resistance evolution against host‐directed antiviral agents: buffalopox virus switches to use p38‐ϒ under long‐term selective pressure of an inhibitor targeting p38‐α. Mol Biol Evol. 2022;39(9):msac177. doi:10.1093/molbev/msac177
Biasini M, Bienert S, Waterhouse A, et al. SWISS‐MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 2014;42(W1):W252‐W258.
Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE, Simmerling C. ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J Chem Theory Comput. 2015;11(8):3696‐3713.
Kumar R, Afsar M, Khandelwal N, et al. Emetine suppresses SARS‐CoV‐2 replication by inhibiting interaction of viral mRNA with eIF4E. Antiviral Res. 2021;189:105056.
Eberhardt J, Santos‐Martins D, Tillack AF, Forli S. AutoDock Vina 1.2. 0: new docking methods, expanded force field, and python bindings. J Chem Inf Model. 2021;61(8):3891‐3898.
Wallace AC, Laskowski RA, Thornton JM. LIGPLOT: a program to generate schematic diagrams of protein‐ligand interactions. Protein Eng. 1995;8(2):127‐134.
López‐Blanco JR, Aliaga JI, Quintana‐Ortí ES, Chacón P. iMODS: internal coordinates normal mode analysis server. Nucleic Acids Res. 2014;42(W1):W271‐W276.
Kumar R, Khandelwal N, Thachamvally R, et al. Role of MAPK/MNK1 signaling in virus replication. Virus Res. 2018;253:48‐61.
Siddiqui N, Tempel W, Nedyalkova L, et al. Structural insights into the allosteric effects of 4EBP1 on the eukaryotic translation initiation factor eIF4E. J Mol Biol. 2012;415(5):781‐792.
Tomoo K, Shen X, Okabe K, et al. Crystal structures of 7‐methylguanosine 5′‐triphosphate (m7GTP)‐and P1‐7‐methylguanosine‐P3‐adenosine‐5′,5′‐triphosphate (m7GpppA)‐bound human full‐length eukaryotic initiation factor 4E: biological importance of the C‐terminal flexible region. Biochem J. 2002;362(3):539‐544.
Marennikova SS, Shelukhina EM, Shenkman LS. Role of the temperature of incubation of infected chick embryos in the differentiation of certain poxviruses according to pock morphology. Acta Virol. 1973;17(4):362.
Baxby D. Variability in the characteristics of pocks produced on the chick chorioallantois by white pock mutants of cowpox and other poxviruses. J Hyg. 1969;67(4):637‐647.
Castrillo M, Córdova T, Cabrera G, Rodríguez‐Ortega M. Effect of naringenin, hesperetin and their glycosides forms on the replication of the 17D strain of yellow fever virus. Av Biomed. 2015;4(2):69‐78.
Ding P, Summers MF. Sequestering the 5'‐cap for viral RNA packaging. BioEssays. 2022;44(11):e2200104.
Kumar R, Khandelwal N, Chander Y, et al. MNK1 inhibitor as an antiviral agent suppresses buffalopox virus protein synthesis. Antiviral Res. 2018;160:126‐136.
Kim GD. Hesperetin inhibits vascular formation by suppressing of the PI3K/AKT, ERK, and p38 MAPK signaling pathways. Prev Nutr Food Sci. 2014;19(4):299‐306.
Jo SH, Kim ME, Cho JH, et al. Hesperetin inhibits neuroinflammation on microglia by suppressing inflammatory cytokines and MAPK pathways. Arch Pharmacal Res. 2019;42:695‐703.
Palit S, Kar S, Sharma G, Das PK. Hesperetin induces apoptosis in breast carcinoma by triggering accumulation of ROS and activation of ASK1/JNK pathway. J Cell Physiol. 2015;230(8):1729‐1739.
Kim JY, Jung KJ, Choi JS, Chung HY. Modulation of the age‐related nuclear factor‐κB (NF‐κB) pathway by hesperetin. Aging Cell. 2006;5(5):401‐411.
Yang Y, Wolfram J, Shen H, Fang X, Ferrari M. Hesperetin: an inhibitor of the transforming growth factor‐β (TGF‐β) signaling pathway. Eur J Med Chem. 2012;58:390‐395.
Donaldson EF, Deming DJ, O'Rear JJ, Naeger LK. Regulatory evaluation of antiviral drug resistance in the era of next‐generation sequencing. Biomark Med. 2015;9(11):1047‐1051.
Kumar R, Barua S, Tripathi BN, Kumar N. Role of ROCK signaling in virus replication. Virus Res. 2023;329:199105.
Kumar N, Xin Z, Liang Y, Ly H, Liang Y. NF‐κB signaling differentially regulates influenza virus RNA synthesis. J Virol. 2008;82(20):9880‐9889.
Kumar N, Sharma S, Kumar R, et al. Host‐directed antiviral therapy. Clin Microbiol Rev. 2020;33(3):e00168‐19. doi:10.1128/CMR.00168-19
Chander Y, Kumar R, Khandelwal N, et al. Role of p38 mitogen‐activated protein kinase signalling in virus replication and potential for developing broad spectrum antiviral drugs. Rev Med Virol. 2021;31(5):1‐16.
Kumar N, Barua S, Thachamvally R, Tripathi BN. Systems perspective of morbillivirus replication. Microbial Physiol. 2016;26(6):389‐400.
Kumar R, Chander Y, Khandelwal N, et al. ROCK1/MLC2 inhibition induces decay of viral mRNA in BPXV infected cells. Sci Rep. 2022;12(1):17811.
Kumar R, Khandelwal N, Chander Y, et al. S‐adenosylmethionine‐dependent methyltransferase inhibitor DZNep blocks transcription and translation of SARS‐CoV‐2 genome with a low tendency to select for drug‐resistant viral variants. Antiviral Res. 2022;197:105232.
Kumar N, Khandelwal N, Kumar R, et al. Inhibitor of sarco/endoplasmic reticulum calcium‐ATPase impairs multiple steps of paramyxovirus replication. Front Microbiol. 2019;10:209.
Kumar N, Sharma NR, Ly H, Parslow TG, Liang Y. Receptor tyrosine kinase inhibitors that block replication of influenza a and other viruses. Antimicrob Agents Chemother. 2011;55(12):5553‐5559.
Kumar N, Liang Y, Parslow TG, Liang Y. Receptor tyrosine kinase inhibitors block multiple steps of influenza a virus replication. J Virol. 2011;85(6):2818‐2827.