How glycobiology can help us treat and beat the COVID-19 pandemic

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged during the last months of 2019, spreading throughout the world as a highly transmissible infectious illness designated as COVID-19. Vaccines have now appeared, but the challenges in producing sufficient material and distributing them around the world means that effective treatments to limit infection and improve recovery are still urgently needed. This review focuses on the relevance of different glycobiological molecules that could potentially serve as or inspire therapeutic tools during SARS-CoV-2 infection. As such, we highlight the glycobiology of the SARS-CoV-2 infection process, where glycans on viral proteins and on host glycosaminoglycans have critical roles in efficient infection. We also take notice of the glycan-binding proteins involved in the infective capacity of virus and in human defense. In addition, we critically evaluate the glycobiological contribution of candidate drugs for COVID-19 therapy such as glycans for vaccines, anti-glycan antibodies, recombinant lectins, lectin inhibitors, glycosidase inhibitors, polysaccharides, and numerous glycosides, emphasizing some opportunities to repurpose FDA-approved drugs. For the next-generation drugs suggested here, biotechnological engineering of new probes to block the SARS-CoV-2 infection might be based on the essential glycobiological insight on glycosyltransferases, glycans, glycan-binding proteins, and glycosidases related to this pathology.

Keywords: COVID-19; FDA-approved drugs; SARS-CoV-2; glycobiology; potential therapies.

Figure 1

Infective life cycle of SARS-CoV-2. The interaction between the S protein and ACE2 receptor allows the attachment of the virus to the host cell (1). After that, the entry can be achieved by endocytosis (2) or by fusion of the viral and cellular membranes (3). Once inside, the viral RNA begins to be translated for producing the 1a and 1ab proteins (4). These proteins undergo subsequent proteolysis to produce nonstructural proteins (nsps), which complex thereafter to form the replicase-transcriptase complex (RTC) (5). The RTC is in charge of synthesizing the new viral RNA (- sense) and the structural viral proteins; both genomic and subgenomic RNAs are produced through negative-strand intermediates (6). At the end of the process, the assembly of the viral particle occurs (7) and the virus is released by exocytosis (8) (2).

Figure 2

Representative scheme of COVID-19 pathogenesis. Trajectory of SARS-CoV-2 shedding; symptoms and adaptive immune response of patients without or with minor airways difficulties and with severe disease (4).

Figure 3

SARS-CoV-2 S glycoprotein–ACE2 interaction. Viral particles attach to the cell membrane through a very specific interaction between the viral spike glycoprotein and ACE2 on host cell surface. PDB models (6M0J and 7A98) were retrieved from (21).

Figure 4

Schematic of SARS-CoV-2 S glycoprotein domains, subunits, and N-/O-glycan sites. The different regions and components are represented along the protein backbone (light blue). Protein domains (shown in different colors) are as follows: SS, signal sequence; NTD, N-terminal domain; RBD, receptor-binding domain; FP, fusion peptide; HR1, heptad repeat 1; CH, central helix; CD, connector domain; HR2, heptad repeat 2; TM, transmembrane domain; CT, cytoplasmic tail. Sites for N-glycosylation (blue) and O-glycosylation (orange) are indicated with their specific amino acid position. The cleavage sites for S1/S2 and S2’ proteases are shown on top (10, 23, 24).

Figure 5

Chemical structural conformation of potential therapeutic drugs. Structural conformers presented as sticks were retrieved from PubChem (https://pubchem.ncbi.nlm.nih.gov).