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It is urgent to develop antiviral compounds with novel targets. Photodynamic therapy shows potential in controlling agricultural pests, but nonselective damage from reactive oxygen species (ROS) unexpectedly affects healthy tissues. A G-quadruplex (G4)-forming sequence in the tobacco mosaic virus (TMV) genome was identified to interfere the RNA replication <jats:italic>in vitro<\/jats:italic>, and affect the proliferation of TMV in tobacco. <jats:italic>N<\/jats:italic>-methyl mesoporphyrin IX stabilizing the G4 structure exhibited inhibition against viral proliferation, which was comparable to the inhibition effect of ribavirin. This indicated that G4 could work as an antiviral target. The large conjugate planes shared by G4 ligands and photosensitizers (PSs) remind us that the PSs could work as antiviral agents by targeting G4 in the genome of TMV. Chlorin e6 (Ce6) was identified to stabilize the G4 structure in the dark and selectively cleave the G4 sequence by producing ROS upon LED-light irradiation, leading to 92.2% inhibition against TMV <jats:italic>in vivo<\/jats:italic>, which is higher than that of commercial ningnanmycin. The inhibition of Ce6 was lost against the mutant variants lacking the G4-forming sequence. These findings indicated that the G-quadruplex in the TMV genome worked as an important structural element regulating viral proliferation, and could act as the antiviral target of photodynamic therapy.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011796","type":"journal-article","created":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T18:48:21Z","timestamp":1701974901000},"page":"e1011796","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["G-quadruplex in the TMV Genome Regulates Viral Proliferation and Acts as Antiviral Target of Photodynamic Therapy"],"prefix":"10.1371","volume":"19","author":[{"given":"Congbao","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianpeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyue","family":"Pei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqi","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daozhong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiqian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhikun","family":"Gui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sisi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9923-789X","authenticated-orcid":true,"given":"Dengguo","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,12,7]]},"reference":[{"key":"ppat.1011796.ref001","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/s41929-022-00823-1","article-title":"Site-selective proteolytic cleavage of plant viruses by photoactive chiral nanoparticles.","volume":"5","author":"R Gao","year":"2022","journal-title":"Nat Catalysis"},{"issue":"5","key":"ppat.1011796.ref002","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nrc1071","article-title":"Photodynamic therapy for cancer","volume":"3","author":"DE Dolmans","year":"2003","journal-title":"Nat Rev Cancer"},{"issue":"7","key":"ppat.1011796.ref003","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41580-020-0230-3","article-title":"Reactive oxygen species (ROS) as pleiotropic physiological signalling agents.","volume":"21","author":"H Sies","year":"2020","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"9","key":"ppat.1011796.ref004","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1111\/jipb.12654","article-title":"Reactive oxygen species signaling and stomatal movement in plant responses to drought stress and pathogen attack","volume":"60","author":"J Qi","year":"2018","journal-title":"J Integr Plant Biol"},{"key":"ppat.1011796.ref005","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1093\/nar\/gkab127","article-title":"Richter SN, Paolo G. 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