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Vaccines have exhibited effectiveness, but their efficacy diminishes over time while new variants continue to emerge. Antiviral medications offer a viable alternative, but their success has been inconsistent. Therefore, there remains an ongoing need to identify innovative antiviral drugs for treating COVID-19 and its post-infection complications. The ORF3a (open reading frame 3a) protein found in SARS-CoV-2, represents a promising target for antiviral treatment due to its multifaceted role in viral pathogenesis, cytokine storms, disease severity, and mortality. ORF3a contributes significantly to viral pathogenesis by facilitating viral assembly and release, essential processes in the viral life cycle, while also suppressing the body\u2019s antiviral responses, thus aiding viral replication. ORF3a also has been implicated in triggering excessive inflammation, characterized by NF-\u03baB-mediated cytokine production, ultimately leading to apoptotic cell death and tissue damage in the lungs, kidneys, and the central nervous system. Additionally, ORF3a triggers the activation of the NLRP3 inflammasome, inciting a cytokine storm, which is a major contributor to the severity of the disease and subsequent mortality. As with the spike protein, ORF3a also undergoes mutations, and certain mutant variants correlate with heightened disease severity in COVID-19. These mutations may influence viral replication and host cellular inflammatory responses. While establishing a direct link between ORF3a and mortality is difficult, its involvement in promoting inflammation and exacerbating disease severity likely contributes to higher mortality rates in severe COVID-19 cases. This review offers a comprehensive and detailed exploration of ORF3a\u2019s potential as an innovative antiviral drug target. Additionally, we outline potential strategies for discovering and developing ORF3a inhibitor drugs to counteract its harmful effects, alleviate tissue damage, and reduce the severity of COVID-19 and its lingering complications.<\/jats:p>","DOI":"10.3390\/pathogens13010075","type":"journal-article","created":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T08:52:03Z","timestamp":1705308723000},"page":"75","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2875-9743","authenticated-orcid":false,"given":"Jiantao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kellie","family":"Hom","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3322-3716","authenticated-orcid":false,"given":"Mohamed","family":"Nasr","sequence":"additional","affiliation":[{"name":"Drug Development and Clinical Sciences Branch, Division of AIDS, NIAID, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6714-1946","authenticated-orcid":false,"given":"Volodymyr","family":"Gerzanich","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5847-3260","authenticated-orcid":false,"given":"Yanjin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, University of Maryland, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6487-2356","authenticated-orcid":false,"given":"Qiyi","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Howard University College of Medicine, Washington, DC 20059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengtian","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5373-1988","authenticated-orcid":false,"given":"J. 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