Targeting Myeloid Differentiation Primary Response Protein 88 (MyD88) and Galectin-3 to Develop Broad-Spectrum Host-Mediated Therapeutics against SARS-CoV-2

• Published in: International journal of molecular sciences Vol. 25; no. 15; p. 8421
• Main Authors: Saikh, Kamal U, Anam, Khairul, Sultana, Halima, Ahmed, Rakin, Kumar, Simran, Srinivasan, Sanjay, Ahmed, Hafiz
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.08.2024
• Subjects: Animals; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; B cells; Cellular signal transduction; Coronaviruses; COVID-19; COVID-19 - immunology; COVID-19 - virology; COVID-19 Drug Treatment; cytokine; Cytokine storm; Development and progression; Disease; Drug discovery; Galectin 3 - metabolism; galectin-3; Humans; IFNs; Immune response; Immunity, Innate; Infections; Interferon; Kinases; Medical research; Medicine, Experimental; MyD88; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Pathogens; Proteins; SARS-CoV-2; SARS-CoV-2 - immunology; SARS-CoV-2 - physiology; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signal Transduction; Vaccines; Viral infections; COVID-19; IFNs; cytokine; PRR; SARS-CoV-2; NLRP3; MyD88; galectin-3; TLRs
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25158421

Nearly six million people worldwide have died from the coronavirus disease (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although COVID-19 vaccines are largely successful in reducing the severity of the disease and deaths, the decline in vaccine-induced immunity over time and the continuing emergence of new viral variants or mutations underscore the need for an alternative strategy for developing broad-spectrum host-mediated therapeutics against SARS-CoV-2. A key feature of severe COVID-19 is dysregulated innate immune signaling, culminating in a high expression of numerous pro-inflammatory cytokines and chemokines and a lack of antiviral interferons (IFNs), particularly type I (alpha and beta) and type III (lambda). As a natural host defense, the myeloid differentiation primary response protein, MyD88, plays pivotal roles in innate and acquired immune responses via the signal transduction pathways of Toll-like receptors (TLRs), a type of pathogen recognition receptors (PRRs). However, recent studies have highlighted that infection with viruses upregulates MyD88 expression and impairs the host antiviral response by negatively regulating type I IFN. Galectin-3 (Gal3), another key player in viral infections, has been shown to modulate the host immune response by regulating viral entry and activating TLRs, the NLRP3 inflammasome, and NF-κB, resulting in the release of pro-inflammatory cytokines and contributing to the overall inflammatory response, the so-called "cytokine storm". These studies suggest that the specific inhibition of MyD88 and Gal3 could be a promising therapy for COVID-19. This review presents future directions for MyD88- and Gal3-targeted antiviral drug discovery, highlighting the potential to restore host immunity in SARS-CoV-2 infections.