{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:23:15Z","timestamp":1786116195267,"version":"build-2736575974"},"reference-count":109,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001804","name":"Canada Research Chair on plant specialized metabolism","doi-asserted-by":"publisher","award":["CRC-2023 00353"],"award-info":[{"award-number":["CRC-2023 00353"]}],"id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]},{"award":["CRC-2023 00353"],"award-info":[{"award-number":["CRC-2023 00353"]}],"id":[{"id":"https:\/\/ror.org\/0517h6h17","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Neglected arboviruses dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and chikungunya collectively affect hundreds of millions of people annually, yet no specific antiviral drug has been approved for any of them. Alkaloids, nitrogen-containing specialized metabolites produced by diverse plant families, have emerged as a promising source of broad-spectrum antiviral scaffolds. This review compiles and critically analyzes over 100 alkaloid-virus pairs across several RNA virus families, providing a comparative mechanistic analysis. Lycorine, narciclasine, emetine, and berbamine, among others, exhibit potent activity against phylogenetically distant viruses, with the most potent activities reported against flaviviruses (narciclasine: EC50 0.02 \u00b5M against DENV, ZIKV, YFV, and JEV; pancratistatine: 0.0063 \u00b5M against ZIKV). Structure-activity analysis of multiple alkaloid classes identifies key pharmacophoric features, including the phenanthridine nucleus (lycorine derivatives) and the bis-benzylisoquinoline scaffold (tetrandrine, berbamine), as determinants of antiviral potency, selectivity, and broad-spectrum activity. Genetic resistance data in West Nile virus challenge the widely accepted model of lycorine as a direct nucleoside inhibitor, instead pointing toward the involvement of the membrane-associated NS4A-2K-NS4B replication complex, though direct validation remains limited for other flaviviruses. Converging structural, biochemical, and transcriptomic evidence suggests that ribosome-mediated translational stress may represent an additional host-directed antiviral mechanism for isoquinoline-type alkaloids, though the causal chain from ribosome binding to activation of the integrated stress response and to antiviral effect has not been established. The present analysis highlights that in vivo validation remains limited to a few alkaloid-virus pairs. Unbiased target deconvolution and formal testing of the ribosome\/integrated stress response hypothesis stand out as essential research priorities.<\/jats:p>","DOI":"10.3390\/molecules31152728","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T08:08:02Z","timestamp":1786003682000},"page":"2728","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cross-Family Mechanistic Analysis of Plant Alkaloids Against Neglected Arboviruses and Related RNA Viruses"],"prefix":"10.3390","volume":"31","author":[{"given":"Marcia","family":"R\u00e9gis","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Chemistry, Physics, and Forensic Science, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, Trois-Rivi\u00e8res, QC G9A 5H7, Canada"},{"name":"Plant Biology Research Group, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, Trois-Rivi\u00e8res, QC G9A 5H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario Fernando","family":"Sanchez Moreno","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Chemistry, Physics, and Forensic Science, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, Trois-Rivi\u00e8res, QC G9A 5H7, Canada"},{"name":"Plant Biology Research Group, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, Trois-Rivi\u00e8res, QC G9A 5H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7046-6194","authenticated-orcid":false,"given":"Hugo","family":"Germain","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Chemistry, Physics, and Forensic Science, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, Trois-Rivi\u00e8res, QC G9A 5H7, Canada"},{"name":"Plant Biology Research Group, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, Trois-Rivi\u00e8res, QC G9A 5H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6235-6465","authenticated-orcid":false,"given":"Natacha","family":"M\u00e9rindol","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Chemistry, Physics, and Forensic Science, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, Trois-Rivi\u00e8res, QC G9A 5H7, Canada"},{"name":"Plant Biology Research Group, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, Trois-Rivi\u00e8res, QC G9A 5H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4355-5503","authenticated-orcid":false,"given":"Isabel","family":"Desgagn\u00e9-Penix","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Chemistry, Physics, and Forensic Science, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, Trois-Rivi\u00e8res, QC G9A 5H7, Canada"},{"name":"Plant Biology Research Group, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, Trois-Rivi\u00e8res, QC G9A 5H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3418","DOI":"10.1038\/s41467-025-58609-5","article-title":"The overlapping global distribution of dengue, chikungunya, Zika and yellow fever","volume":"16","author":"Lim","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_2","unstructured":"World Health Organization (2026, May 22). Dengue and Severe Dengue. Available online: https:\/\/www.who.int\/fr\/news-room\/fact-sheets\/detail\/dengue-and-severe-dengue."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1002\/cmdc.201300505","article-title":"Anti-dengue-virus activity and structure-activity relationship studies of lycorine derivatives","volume":"9","author":"Wang","year":"2014","journal-title":"ChemMedChem"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/s41584-019-0276-9","article-title":"Rheumatic manifestations of chikungunya: Emerging concepts and interventions","volume":"15","author":"Suhrbier","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41572-023-00429-2","article-title":"Chikungunya fever","volume":"9","author":"Bartholomeeusen","year":"2023","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_6","unstructured":"World Health Organization (2026, May 22). The History of Zika Virus. Available online: https:\/\/www.who.int\/news-room\/feature-stories\/detail\/the-history-of-zika-virus."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1128\/CMR.00072-15","article-title":"Zika virus","volume":"29","author":"Musso","year":"2016","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e257","DOI":"10.1016\/S2214-109X(23)00522-3","article-title":"Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4.5-year results from a phase 3, randomised, double-blind, placebo-controlled trial","volume":"12","author":"Tricou","year":"2024","journal-title":"Lancet Glob. Health"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1038\/s41591-026-04255-3","article-title":"Long-term efficacy and safety of the single-dose tetravalent Butantan dengue vaccine","volume":"32","author":"Moreira","year":"2026","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1016\/S0140-6736(23)00641-4","article-title":"Safety and immunogenicity of a single-shot live-attenuated chikungunya vaccine: A double-blind, multicentre, randomised, placebo-controlled, phase 3 trial","volume":"401","author":"Schneider","year":"2023","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1056\/NEJMoa2500179","article-title":"Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model","volume":"393","author":"Durbin","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6080","DOI":"10.1038\/s41467-024-50437-3","article-title":"Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B\/NS3 and blocks replication organelle formation","volume":"15","author":"Kiemel","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hatzakis, A. (2021). Hepatitis C: Care and Treatment, Springer.","DOI":"10.1007\/978-3-030-67762-6"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ka, S., Koirala, M., Merindol, N., and Desgagne-Penix, I. (2020). Biosynthesis and Biological Activities of Newly Discovered Amaryllidaceae Alkaloids. Molecules, 25.","DOI":"10.3390\/molecules25214901"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.clindermatol.2018.03.005","article-title":"Medicinal plants with traditional use: Ethnobotany in the Indian subcontinent","volume":"36","author":"Rupani","year":"2018","journal-title":"Clin. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s13659-022-00366-9","article-title":"Alkaloids as potential antivirals. A comprehensive review","volume":"13","author":"Faisal","year":"2023","journal-title":"Nat. Prod. Bioprospect."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s11101-020-09678-5","article-title":"Biosynthesis of alkaloids in Amaryllidaceae plants: A review","volume":"20","year":"2021","journal-title":"Phytochem. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1080\/00378941.1958.10837879","article-title":"Les alcalo\u00efdes dans les plantes","volume":"105","year":"1958","journal-title":"Bull. De La Soci\u00e9t\u00e9 Bot. De Fr."},{"key":"ref_19","unstructured":"Covis, R. (2023). Les alcalo\u00efdes, un moyen de d\u00e9fense chez les plantes et des vertus th\u00e9rapeutiques chez l\u2019homme. Lemag\u2019, 41\u201344."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev.arplant.52.1.29","article-title":"Alkaloid Biosynthesis In Plants: Biochemistry, Cell Biology, Molecular Regulation, and Metabolic Engineering Applications","volume":"52","author":"Facchini","year":"2001","journal-title":"Annu. Rev. Plant Physiol. Plant Mol. Biol."},{"key":"ref_21","unstructured":"Hesse, M. (2002). Alkaloids: Nature\u2019s Curse or Blessing?;, John Wiley & Sons."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Dey, P., Kundu, A., Kumar, A., Gupta, M., Lee, B.M., Bhakta, T., Dash, S., and Kim, H.S. (2020). Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids). Recent Advances in Natural Products Analysis, Elsevier.","DOI":"10.1016\/B978-0-12-816455-6.00015-9"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1039\/c005378c","article-title":"Trends for diverse production strategies of plant medicinal alkaloids","volume":"27","author":"Yang","year":"2010","journal-title":"Nat. Prod. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Amirkia, V., and Heinrich, M. (2014). Alkaloids as drug leads\u2014A predictive structural and biodiversity-based analysis. Phytochem. Lett., 10.","DOI":"10.1016\/j.phytol.2014.06.015"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sung, C., Wei, Y., Watanabe, S., Lee, H.S., Khoo, Y.M., Fan, L., Rathore, A.P., Chan, K.W., Choy, M.M., and Kamaraj, U.S. (2016). Extended Evaluation of Virological, Immunological and Pharmacokinetic Endpoints of CELADEN: A Randomized, Placebo-Controlled Trial of Celgosivir in Dengue Fever Patients. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004851"},{"key":"ref_26","first-page":"431","article-title":"Le pouvoir antiviral des alcalo\u00efdes de v\u00e9g\u00e9taux contre les virus \u00e0 ARN","volume":"26","author":"Girard","year":"2022","journal-title":"Virologie"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/boj.12005","article-title":"The taxonomy and systematics of Apocynaceae: Where we stand in 2012","volume":"171","author":"Nazar","year":"2013","journal-title":"Bot. J. Linn. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e0234920","DOI":"10.1128\/AAC.02349-20","article-title":"A Novel Series of Indole Alkaloid Derivatives Inhibit Dengue and Zika Virus Infection by Interference with the Viral Replication Complex","volume":"65","author":"Fikatas","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.sajb.2023.02.028","article-title":"Global distribution of the chemical constituents and antibacterial activity of essential oils in Lauraceae family: A review","volume":"155","author":"Farias","year":"2023","journal-title":"S. Afr. J. Bot."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1128\/AAC.01467-12","article-title":"Inhibition of chikungunya virus replication by harringtonine, a novel antiviral that suppresses viral protein expression","volume":"57","author":"Kaur","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_31","first-page":"67","article-title":"Activit\u00e9 antimycobact\u00e9rienne extra et intracellulaire de l\u2019\u00e9corce des racines de Berberis hispanica","volume":"149","author":"Hassi","year":"2011","journal-title":"Bull. Soc. Pharm. Bordx."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1002\/chir.22719","article-title":"Amaryllidaceae alkaloids: Absolute configuration and biological activity","volume":"29","author":"Cimmino","year":"2017","journal-title":"Chirality"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5895","DOI":"10.1002\/slct.201601536","article-title":"Total Synthesis of the Natural Product (+)-trans-Dihydronarciclasine via an Asymmetric Organocatalytic [3+3]-Cycloaddition and discovery of its potent anti-Zika Virus (ZIKV) Activity","volume":"1","author":"Revu","year":"2016","journal-title":"ChemistrySelect"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"16562","DOI":"10.1039\/C4RA14666B","article-title":"Biological and pharmacological activities of Amaryllidaceae alkaloids","volume":"5","author":"He","year":"2015","journal-title":"Rsc Adv."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/ptr.2650080217","article-title":"Activity of a methanolic extract of Zimbabwean Crinum macowanii against exotic RNA viruses in vitro","volume":"8","author":"Duri","year":"1994","journal-title":"Phyther. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e0039821","DOI":"10.1128\/AAC.00398-21","article-title":"Amaryllidaceae Alkaloid Cherylline Inhibits the Replication of Dengue and Zika Viruses","volume":"65","author":"Ka","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"150393","DOI":"10.1016\/j.bbrc.2024.150393","article-title":"Inhibition of early RNA replication in Chikungunya and Dengue virus by lycorine: In vitro and in silico studies","volume":"730","author":"Agrawal","year":"2024","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.virol.2008.11.003","article-title":"A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor","volume":"384","author":"Zou","year":"2009","journal-title":"Virology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1021\/np50089a003","article-title":"Antiviral (RNA) activity of selected Amaryllidaceae isoquinoline constituents and synthesis of related substances","volume":"55","author":"Gabrielsen","year":"1992","journal-title":"J. Nat. Prod."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Masi, M., Di Lecce, R., Merindol, N., Girard, M.P., Berthoux, L., Desgagne-Penix, I., Calabro, V., and Evidente, A. (2022). Cytotoxicity and Antiviral Properties of Alkaloids Isolated from Pancratium maritimum. Toxins, 14.","DOI":"10.3390\/toxins14040262"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e42580","DOI":"10.1016\/j.heliyon.2025.e42580","article-title":"Antiviral alkaloids from Crinum jagus: Extraction, synergistic effects, and activity against dengue virus and human coronavirus OC43","volume":"11","author":"Jayawardena","year":"2025","journal-title":"Heliyon"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12985-022-01751-z","article-title":"Searching for plant-derived antivirals against dengue virus and Zika virus","volume":"19","author":"Alves","year":"2022","journal-title":"Virol. J."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sakai, R., Sato, K., Tsugita, A., Thaveepornkul, L., Takada, A., Miyamoto, H., Kurokawa, R., Yoshida, M., Yokoyama, T., and Evidente, A. (2025). Modulation of translational elongation by montanine alkaloids preferentially inhibits RNA viruses. bioRxiv.","DOI":"10.64898\/2025.12.19.695327"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.virs.2024.09.001","article-title":"Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy","volume":"39","author":"Huang","year":"2024","journal-title":"Virol. Sin."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Giannone, D.A., Piccini, L.E., Brunetti, J.E., Quintana, V.M., Damonte, E.B., and Castilla, V. (2023). Berberine inhibitory action against zika and dengue viruses in cell cultures. Acta Virol., 67.","DOI":"10.3389\/av.2023.11931"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8698","DOI":"10.1128\/JVI.79.14.8698-8706.2005","article-title":"Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo","volume":"79","author":"Whitby","year":"2005","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"62","DOI":"10.4172\/jaa.1000009","article-title":"Antiviral activity of emetine dihydrochloride against dengue virus infection","volume":"1","author":"Chen","year":"2009","journal-title":"J. Antivir. Antiretrovir."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Hishiki, T., Kato, F., Tajima, S., Toume, K., Umezaki, M., Takasaki, T., and Miura, T. (2017). Hirsutine, an Indole Alkaloid of Uncaria rhynchophylla, Inhibits Late Step in Dengue Virus Lifecycle. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.01674"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.antiviral.2018.11.011","article-title":"Tomatidine, a novel antiviral compound towards dengue virus","volume":"161","author":"Troost","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41421-018-0034-1","article-title":"Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: Inhibiting viral replication and decreasing viral entry","volume":"4","author":"Yang","year":"2018","journal-title":"Cell Discov."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.antiviral.2015.12.012","article-title":"Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses","volume":"126","author":"Varghese","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1007\/s12250-021-00438-z","article-title":"In Vitro Inhibition of Alphaviruses by Lycorine","volume":"36","author":"Li","year":"2021","journal-title":"Virol. Sin."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Troost-Kind, B., van Hemert, M.J., van de Pol, D., van der Ende-Metselaar, H., Merits, A., Borggrewe, M., Rodenhuis-Zybert, I.A., and Smit, J.M. (2021). Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression. PLoS Negl. Trop. Dis., 15.","DOI":"10.1371\/journal.pntd.0009916"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Sharma, A., Subramani, C., Shouri, K., Sharma, G., Basu, B., Pandey, A.D., Rout, A., Sharma, D., Jain, D., and Vrati, S. (2025). Emetine dihydrochloride inhibits Chikungunya virus nsP2 helicase and shows antiviral activity in the cell culture and mouse model of virus infection. bioRxiv.","DOI":"10.1101\/2025.06.20.660672"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"154480","DOI":"10.1016\/j.phymed.2022.154480","article-title":"Antiviral alkaloid principles of the plant family Amaryllidaceae","volume":"108","author":"Nair","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Abookleesh, F.L., Al-Anzi, B.S., and Ullah, A. (2022). Potential Antiviral Action of Alkaloids. Molecules, 27.","DOI":"10.3390\/molecules27030903"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"11555","DOI":"10.1128\/JVI.79.18.11555-11558.2005","article-title":"Adaptive value of high mutation rates of RNA viruses: Separating causes from consequences","volume":"79","author":"Elena","year":"2005","journal-title":"J. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4433","DOI":"10.1007\/s00018-016-2299-6","article-title":"Mechanisms of viral mutation","volume":"73","author":"Sanjuan","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"561","DOI":"10.4155\/fmc.15.14","article-title":"Lycorine-derived phenanthridine downregulators of host Hsc70 as potential hepatitis C virus inhibitors","volume":"7","author":"Chen","year":"2015","journal-title":"Future Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.phymed.2018.09.025","article-title":"Berberine inhibits hepatitis C virus entry by targeting the viral E2 glycoprotein","volume":"53","author":"Hung","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e20141","DOI":"10.1016\/j.heliyon.2023.e20141","article-title":"Alpha-mangostin, piperine and beta-sitosterol as hepatitis C antivirus (HCV): In silico and in vitro studies","volume":"9","author":"Saputro","year":"2023","journal-title":"Heliyon"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3527","DOI":"10.1021\/acsptsci.4c00424","article-title":"Amaryllidaceae Alkaloids Screen Unveils Potent Anticoronaviral Compounds and Associated Structural Determinants","volume":"7","author":"Merindol","year":"2024","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Yang, C.W., Lee, Y.Z., Hsu, H.Y., Jan, J.T., Lin, Y.L., Chang, S.Y., Peng, T.T., Yang, R.B., Liang, J.J., and Liao, C.C. (2020). Inhibition of SARS-CoV-2 by Highly Potent Broad-Spectrum Anti-Coronaviral Tylophorine-Based Derivatives. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.606097"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Kim, D.E., Min, J.S., Jang, M.S., Lee, J.Y., Shin, Y.S., Song, J.H., Kim, H.R., Kim, S., Jin, Y.H., and Kwon, S. (2019). Natural Bis-Benzylisoquinoline Alkaloids-Tetrandrine, Fangchinoline, and Cepharanthine, Inhibit Human Coronavirus OC43 Infection of MRC-5 Human Lung Cells. Biomolecules, 9.","DOI":"10.3390\/biom9110696"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e00023-19","DOI":"10.1128\/JVI.00023-19","article-title":"High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses","volume":"93","author":"Shen","year":"2019","journal-title":"J. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e70715","DOI":"10.1002\/mco2.70715","article-title":"Lycorine Derivative Inhibits SARS-CoV-2 Replication by Reducing -1 Programmed Ribosomal Frameshifting via Targeting ZAP","volume":"7","author":"Du","year":"2026","journal-title":"MedComm"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"111347","DOI":"10.1016\/j.isci.2024.111347","article-title":"Berbamine prevents SARS-CoV-2 entry and transmission","volume":"27","author":"Sadhu","year":"2024","journal-title":"iScience"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"104786","DOI":"10.1016\/j.antiviral.2020.104786","article-title":"Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro","volume":"178","author":"Choy","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1080\/22221751.2020.1772676","article-title":"Gemcitabine, lycorine and oxysophoridine inhibit novel coronavirus (SARS-CoV-2) in cell culture","volume":"9","author":"Zhang","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"101873","DOI":"10.1016\/j.tmaid.2020.101873","article-title":"Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation","volume":"37","author":"Gendrot","year":"2020","journal-title":"Travel Med. Infect. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.antiviral.2005.02.007","article-title":"Identification of natural compounds with antiviral activities against SARS-associated coronavirus","volume":"67","author":"Li","year":"2005","journal-title":"Antivir. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"153440","DOI":"10.1016\/j.phymed.2020.153440","article-title":"Lycorine, a non-nucleoside RNA dependent RNA polymerase inhibitor, as potential treatment for emerging coronavirus infections","volume":"86","author":"Jin","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ceca.2018.08.003","article-title":"NAADP-dependent Ca2+ signaling regulates Middle East respiratory syndrome-coronavirus pseudovirus translocation through the endolysosomal system","volume":"75","author":"Gunaratne","year":"2018","journal-title":"Cell Calcium"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/s41586-021-03703-z","article-title":"A condensate-hardening drug blocks RSV replication in vivo","volume":"595","author":"Galloux","year":"2021","journal-title":"Nature"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"396","DOI":"10.3109\/13880209.2010.519390","article-title":"Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids","volume":"49","author":"Ozcelik","year":"2011","journal-title":"Pharm. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1002\/ptr.751","article-title":"Inhibitory effects of Korean plants on HIV-1 activities","volume":"15","author":"Min","year":"2001","journal-title":"Phytother. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1021\/np9700679","article-title":"Michellamines D-F, new HIV-inhibitory dimeric naphthylisoquinoline alkaloids, and korupensamine E, a new antimalarial monomer, from Ancistrocladus korupensis","volume":"60","author":"Hallock","year":"1997","journal-title":"J. Nat. Prod."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1055\/s-2004-827227","article-title":"Anti-HIV-1 activity of the Iboga alkaloid congener 18-methoxycoronaridine","volume":"70","author":"Silva","year":"2004","journal-title":"Planta Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/j.1749-6632.1990.tb17831.x","article-title":"Inhibition of glycoprotein processing and HIV replication by castanospermine analogues","volume":"616","author":"Sunkara","year":"1990","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1021\/acsmedchemlett.5b00339","article-title":"Aloperine and its derivatives as a new class of HIV-1 entry inhibitors","volume":"7","author":"Dang","year":"2016","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1248\/cpb.50.1195","article-title":"Sesquiterpenes and alkaloids from Lindera chunii and their inhibitory activities against HIV-1 integrase","volume":"50","author":"Zhang","year":"2002","journal-title":"Chem. Pharm. Bull."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Wan, Z., Lu, Y., Liao, Q., Wu, Y., and Chen, X. (2012). Fangchinoline inhibits human immunodeficiency virus type 1 replication by interfering with gp160 proteolytic processing. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039225"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"11474","DOI":"10.3390\/molecules200611474","article-title":"Natural Plant Alkaloid (Emetine) Inhibits HIV-1 Replication by Interfering with Reverse Transcriptase Activity","volume":"20","author":"Abreu","year":"2015","journal-title":"Molecules"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2872","DOI":"10.1016\/j.bmc.2010.03.015","article-title":"Synthesis and anti-HIV activity of alkylated quinoline 2,4-diols","volume":"18","author":"Ahmed","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acsinfecdis.4c00600","article-title":"Fangchinoline Inhibits Zika Virus by Disrupting Virus Internalization","volume":"10","author":"Yang","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"199030","DOI":"10.1016\/j.virusres.2022.199030","article-title":"Cepharanthine inhibits dengue virus production and cytokine secretion","volume":"325","author":"Phumesin","year":"2023","journal-title":"Virus Res."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Gomez-Calderon, C., Mesa-Castro, C., Robledo, S., Gomez, S., Bolivar-Avila, S., Diaz-Castillo, F., and Martinez-Gutierrez, M. (2017). Antiviral effect of compounds derived from the seeds of Mammea americana and Tabernaemontana cymosa on Dengue and Chikungunya virus infections. BMC Complement. Altern. Med., 17.","DOI":"10.1186\/s12906-017-1562-1"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Monsalve-Escudero, L.M., Loaiza-Cano, V., Zapata-Cardona, M.I., Quintero-Gil, D.C., Hernandez-Mira, E., Pajaro-Gonzalez, Y., Oliveros-Diaz, A.F., Diaz-Castillo, F., Quinones, W., and Robledo, S. (2021). The Antiviral and Virucidal Activities of Voacangine and Structural Analogs Extracted from Tabernaemontana cymosa Depend on the Dengue Virus Strain. Plants, 10.","DOI":"10.3390\/plants10071280"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1111\/irv.12035","article-title":"Amaryllidaceae alkaloids inhibit nuclear-to-cytoplasmic export of ribonucleoprotein (RNP) complex of highly pathogenic avian influenza virus H5N1","volume":"7","author":"He","year":"2013","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.virol.2020.04.009","article-title":"Antiviral activity of lycorine against Zika virus in vivo and in vitro","volume":"546","author":"Chen","year":"2020","journal-title":"Virology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"110072","DOI":"10.1016\/j.bioorg.2026.110072","article-title":"Structure-activity relationship of lycorine scaffolds reveals translation inhibition as a determinant of broad-spectrum antiviral activity","volume":"180","author":"Merindol","year":"2026","journal-title":"Bioorg. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/s42003-022-03090-9","article-title":"Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay","volume":"5","author":"Narayanan","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1128\/jvi.67.4.2327-2335.1993","article-title":"Cleavage at a novel site in the NS4A region by the yellow fever virus NS2B-3 proteinase is a prerequisite for processing at the downstream 4A\/4B signalase site","volume":"67","author":"Lin","year":"1993","journal-title":"J. Virol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/s41586-021-03990-6","article-title":"A pan-serotype dengue virus inhibitor targeting the NS3-NS4B interaction","volume":"598","author":"Kaptein","year":"2021","journal-title":"Nature"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.antiviral.2010.08.009","article-title":"Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus","volume":"88","author":"Yang","year":"2010","journal-title":"Antivir. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/0005-2787(76)90261-6","article-title":"Inhibitors of protein synthesis in eukaryotic cells. Comparative effects of some amaryllidaceae alkaloids","volume":"425","author":"Jimenez","year":"1976","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0014-5793(83)80951-X","article-title":"Peptidyltransferase center of ribosomes. On the mechanism of action of alkaloid lycorine","volume":"160","author":"Kukhanova","year":"1983","journal-title":"FEBS Lett."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nature13737","article-title":"Structural basis for the inhibition of the eukaryotic ribosome","volume":"513","author":"Prokhorova","year":"2014","journal-title":"Nature"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Pellegrino, S., Meyer, M., Zorbas, C., Bouchta, S.A., Saraf, K., Pelly, S.C., Yusupova, G., Evidente, A., Mathieu, V., and Kornienko, A. (2018). The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth. Structure, 26.","DOI":"10.1016\/j.str.2018.01.009"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1593\/neo.07535","article-title":"The Amaryllidaceae isocarbostyril narciclasine induces apoptosis by activation of the death receptor and\/or mitochondrial pathways in cancer cells but not in normal fibroblasts","volume":"9","author":"Dumont","year":"2007","journal-title":"Neoplasia"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Le, N.T., De Jonghe, S., Erven, K., Vermeyen, T., Balde, A.M., Herrebout, W.A., Neyts, J., Pannecouque, C., Pieters, L., and Tuenter, E. (2023). Anti-SARS-CoV-2 Activity and Cytotoxicity of Amaryllidaceae Alkaloids from Hymenocallis littoralis. Molecules, 28.","DOI":"10.3390\/molecules28073222"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1038\/s41598-023-28691-0","article-title":"Truncated ring-A amaryllidaceae alkaloid modulates the host cell integrated stress response, exhibiting antiviral activity to HSV-1 and SARSCoV-2","volume":"13","author":"McNulty","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"121614","DOI":"10.1016\/j.jep.2026.121614","article-title":"Lycorine from Lycoris radiata attenuates IBV-induced pathogenicity by boosting MDA5-dependent type I interferon response","volume":"365","author":"Huang","year":"2026","journal-title":"J. Ethnopharmacol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.antiviral.2016.03.017","article-title":"An inducible heat shock protein 70 small molecule inhibitor demonstrates anti-dengue virus activity, validating Hsp70 as a host antiviral target","volume":"130","author":"Howe","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1128\/JVI.79.8.4557-4567.2005","article-title":"Heat shock protein 90 and heat shock protein 70 are components of dengue virus receptor complex in human cells","volume":"79","author":"Medina","year":"2005","journal-title":"J. Virol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Yan, H., Wang, H., Wang, K., Wu, S., Jiang, J., and Li, Y. (2025). Lycorine Inhibits Influenza Virus Replication by Affecting Nascent Nucleoporin Nup93 Synthesis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115358"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1016\/j.phymed.2016.10.008","article-title":"How do the alkaloids emetine and homoharringtonine kill trypanosomes? An insight into their molecular modes of action","volume":"23","author":"Krstin","year":"2016","journal-title":"Phytomedicine"},{"key":"ref_108","first-page":"1","article-title":"Molecular modes of action of cytotoxic alkaloids: From DNA intercalation, spindle poisoning, topoisomerase inhibition to apoptosis and multiple drug resistance","volume":"64","author":"Wink","year":"2007","journal-title":"Alkaloids Chem. Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1093\/nar\/gkw878","article-title":"Activation of cGAS-dependent antiviral responses by DNA intercalating agents","volume":"45","author":"Pepin","year":"2017","journal-title":"Nucleic Acids Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2728\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T08:08:41Z","timestamp":1786003721000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2728"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":109,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["molecules31152728"],"URL":"https:\/\/doi.org\/10.3390\/molecules31152728","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]}}}