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Due to lack of antiviral agents and significant adverse effects and less affordability of vaccines, the E\u2010protein targeted drug development is gaining critical attention among the researchers. The present review explores the structural and genomic diversities of E\u2010protein among animal viruses with special interest to flaviviruses, coronaviruses, and herpesviruses. E\u2010protein's viroporin activity damages host cell membrane and induces inflammation that advances the disease progression. The review also explains the viroporin\u2010mediated NOD\u2010like receptor family pyrin domain\u2010containing 3 (NLRP3), Toll\u2010like receptors (TLRs), nucleotide\u2010binding oligomerisation domain (NOD)\u2010like receptors (NLRs), and retinoic acid\u2010inducible gene I (RIG\u2010I)\u2010like receptors (RLRs)\u2010linked cellular mechanisms in virus\u2010mediated inflammation. The E\u2010protein is considered an alternative promising antiviral target as its functional domain is conserved. This review further enlists the natural, and synthetic inhibitors of E\u2010protein in the development of antiviral agents based on computational, in vitro, and in vivo studies. The E\u2010protein's universal conservation ability to fasten to cellular membranes and limited structural data imparts significant challenge to selective drug inhibition. The present review highlights that the E\u2010protein together with multiple viral factors will boost treatment performance while minimising viral resistance. In addition, broad\u2010range inhibitors targeting E\u2010proteins have the potential to produce single treatment solutions in combating viral infections including several viral strains. In conclusion, E\u2010protein targeted drug would be beneficial in developing potential antiviral agents with high drug specificity, and less viral resistance.<\/jats:p>","DOI":"10.1002\/rmv.70067","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T02:44:57Z","timestamp":1755139497000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Crosstalk Between Viral Envelop\u2010E Protein and Host Innate Immune System: Exploring Pharmacological Targets and Agents"],"prefix":"10.1002","volume":"35","author":[{"given":"Satyam","family":"Shekhar","sequence":"first","affiliation":[{"name":"Department of Pharmacy School of Health Sciences Central University of South Bihar  Gaya India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvind","family":"Maurya","sequence":"additional","affiliation":[{"name":"Department of Pharmacy School of Health Sciences Central University of South Bihar  Gaya India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Sandeep","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Health Sciences Central University of Punjab  Bathinda India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subrat Kumar","family":"Bhattamisra","sequence":"additional","affiliation":[{"name":"Department of Pharmacy School of Health Sciences Central University of South Bihar  Gaya India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gireesh Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacy School of Health Sciences Central University of South Bihar  Gaya India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4235-3926","authenticated-orcid":false,"given":"Debapriya","family":"Garabadu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Health Sciences Central University of Punjab  Bathinda India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"e_1_2_17_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579\u2010022\u201000839\u20101"},{"key":"e_1_2_17_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2014.01.009"},{"key":"e_1_2_17_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02325-17"},{"key":"e_1_2_17_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/v15041000"},{"key":"e_1_2_17_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004077"},{"key":"e_1_2_17_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4075"},{"key":"e_1_2_17_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2014.07.024"},{"key":"e_1_2_17_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00705\u2010023\u201005835\u20101"},{"key":"e_1_2_17_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600064"},{"key":"e_1_2_17_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.07086\u201011"},{"key":"e_1_2_17_12_1","doi-asserted-by":"publisher","DOI":"10.1089\/vbz.2013.1407"},{"key":"e_1_2_17_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004447"},{"key":"e_1_2_17_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/v9010014"},{"key":"e_1_2_17_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2014.09.020"},{"key":"e_1_2_17_16_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.000097"},{"key":"e_1_2_17_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00447\u201016"},{"key":"e_1_2_17_18_1","unstructured":"SagripantiJ. 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