{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T07:47:20Z","timestamp":1782200840335,"version":"3.54.5"},"reference-count":231,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T00:00:00Z","timestamp":1694476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1808705"],"award-info":[{"award-number":["1808705"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Hepatitis B virus (HBV) chronically infects millions of people worldwide, which underscores the importance of discovering and designing novel anti-HBV therapeutics to complement current treatment strategies. An underexploited but attractive therapeutic target is \u03b5, a cis-acting regulatory stem-loop RNA situated within the HBV pregenomic RNA (pgRNA). The binding of \u03b5 to the viral polymerase protein (P) is pivotal, as it triggers the packaging of pgRNA and P, as well as the reverse transcription of the viral genome. Consequently, small molecules capable of disrupting this interaction hold the potential to inhibit the early stages of HBV replication. The rational design of such ligands necessitates high-resolution structural information for the \u03b5\u2013P complex or its individual components. While these data are currently unavailable for P, our recent structural elucidation of \u03b5 through solution nuclear magnetic resonance spectroscopy marks a significant advancement in this area. In this review, we provide a brief overview of HBV replication and some of the therapeutic strategies to combat chronic HBV infection. These descriptions are intended to contextualize our recent experimental efforts to characterize \u03b5 and identify \u03b5-targeting ligands, with the ultimate goal of developing novel anti-HBV therapeutics.<\/jats:p>","DOI":"10.3390\/v15091913","type":"journal-article","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T21:34:12Z","timestamp":1694554452000},"page":"1913","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Hepatitis B Virus Epsilon (\u03b5) RNA Element: Dynamic Regulator of Viral Replication and Attractive Therapeutic Target"],"prefix":"10.3390","volume":"15","author":[{"given":"Lukasz T.","family":"Olenginski","sequence":"first","affiliation":[{"name":"Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA"},{"name":"Department of Biochemistry, University of Colorado, Boulder, CO 80309, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solomon K.","family":"Attionu","sequence":"additional","affiliation":[{"name":"Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica N.","family":"Henninger","sequence":"additional","affiliation":[{"name":"Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9685-3689","authenticated-orcid":false,"given":"Regan M.","family":"LeBlanc","sequence":"additional","affiliation":[{"name":"Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Longhini","sequence":"additional","affiliation":[{"name":"Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA"},{"name":"Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA"},{"name":"Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore K.","family":"Dayie","sequence":"additional","affiliation":[{"name":"Center for Biomolecular Structure and Organization, Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/281646a0","article-title":"Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli","volume":"281","author":"Galibert","year":"1979","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/280815a0","article-title":"Nucleotide sequence of the gene coding for the major protein of hepatitis B virus surface antigen","volume":"280","author":"Valenzuela","year":"1979","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1093\/nar\/7.2.335","article-title":"Localization on the viral genome and nucleotide sequence of the gene coding for the two major polypeptides of the Hepatitis B surface antigen (HBs Ag)","volume":"7","author":"Charnay","year":"1979","journal-title":"Nucleic Acids Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/282575a0","article-title":"Hepatitis B virus genes and their expression in E. coli","volume":"282","author":"Pasek","year":"1979","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1128\/jvi.14.2.384-391.1974","article-title":"DNA of a Human Hepatitis B Virus Candidate","volume":"14","author":"Robinson","year":"1974","journal-title":"J. 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