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

Abstract

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.

Keywords: COVID-19; IFNs; MyD88; NLRP3; PRR; SARS-CoV-2; TLRs; cytokine; galectin-3.

Figure 1

Schematic representation of MyD88 primary and tertiary structures. The 3D model of the MyD88 TIR domain and the BB loop region (in dark blue) was adapted from Refs. [12,21]. DD, death domain; ID, intermediary domain; TIR, Toll-interleukin-1 receptor.

Figure 2

Schematic representation showing MyD88-mediated pro-inflammatory response and plausible mechanism of MyD88 inhibition in restoring host-mediated immune responses.

Figure 3

Schematic representation showing primary and tertiary structures of Gal3. The tertiary structure of Gal3 CRD bound to LacNAc (N-acetyllactosamine) was obtained from the NCBI (https://www.ncbi.nlm.nih.gov/Structure/pdb/1KJL, access on 21 May 2024).

Figure 4

Schematic representation showing virus–host cell interactions and Gal3 inhibition blocking viral entry to host cells. Gal3 is believed to play critical role in viral entry to host cells. Interaction between the galectin-like S1-NTD (N-terminal domain of the virus S1 spike protein) and host sialic acids could be critical for viral entry as means of stabilizing the interaction between S1-CTD (C-terminal domain of the virus S1 spike protein) and ACE2. Moreover, host Gal3 may participate in additional interactions with virus spike glycoprotein for further stabilization, contributing to prolonged infection and severity of disease. Therefore, Gal3 inhibition may disrupt attachment of SARS-CoV-2 to cell surface, preventing entry to host cells (adapted from Refs. [72,80]). The SARS-CoV-2 image was taken from the Centers for Disease Control and Prevention (CDC) website (https://stacks.cdc.gov/view/cdc/86942, access on 20 May 2024).

Figure 5

Schematic representation of Gal3-mediated upregulation of pro-inflammatory cytokines and Gal3 inhibition reversing it. During viral infection, Gal3 can interact with TLR4 to elicit NF-κB-mediated pro-inflammatory cytokines. Gal3 can also activate NLRP3 inflammasome, leading to secretion of pro-inflammatory cytokines. However, inhibition of Gal3 can prevent activation of both NF-κB and NLRP3 inflammasome, abrogating pro-inflammatory signaling (according to Ref. [14]). SARS-CoV-2 image was taken from the Centers for Disease Control and Prevention (CDC) (https://stacks.cdc.gov/view/cdc/86942, access one 20 May 2024).

Figure 6

Chemical structures and compositions of MyD88 and Gal3 inhibitors. Structures of compound 1, EM163, and compound 4210 were adapted from Ref. [11]. Structure of T6167923 was adapted from Ref. [21]. Structures of TD139 and GB1211 were adapted from Ref. [117].