학술논문
SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects.
Document Type
Academic Journal
Author
Zhang J; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Hom K; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.; Zhang C; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Nasr M; Drug Development and Clinical Sciences Branch, Division of AIDS, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.; Gerzanich V; Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Zhang Y; Department of Veterinary Medicine, University of Maryland, College Park, MD 20742, USA.; Tang Q; Department of Microbiology, Howard University College of Medicine, Washington, DC 20059, USA.; Xue F; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.; Simard JM; Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Research & Development Service, VA Maryland Health Care System, Baltimore, MD 21201, USA.; Zhao RY; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Research & Development Service, VA Maryland Health Care System, Baltimore, MD 21201, USA.; Department of Microbiology-Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Institute of Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Source
Publisher: MDPI AG Country of Publication: Switzerland NLM ID: 101596317 Publication Model: Electronic Cited Medium: Print ISSN: 2076-0817 (Print) Linking ISSN: 20760817 NLM ISO Abbreviation: Pathogens Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
2076-0817
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 has posed unparalleled challenges due to its rapid transmission, ability to mutate, high mortality and morbidity, and enduring health complications. 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's antiviral responses, thus aiding viral replication. ORF3a also has been implicated in triggering excessive inflammation, characterized by NF-κB-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's 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.