Targeting the glycans: A paradigm for host‐targeted and COVID‐19 drug design

Abstract

There is always a need for new approaches for the control of virus burdens caused by seasonal outbreaks, the emergence of novel viruses with pandemic potential and the development of resistance to current antiviral drugs. The outbreak of the 2019 novel coronavirus‐disease COVID‐19 represented a pandemic threat and declared a public health emergency of international concern. Herein, the role of glycans for the development of new drugs or vaccines, as a host‐targeted approach, is discussed where may provide a front‐line prophylactic or threats to protect against the current and any future respiratory‐infecting virus and possibly against other respiratory pathogens. As a prototype, the role of glycans in the coronavirus infection, as well as, galectins (Gal) as the glycan‐recognition agents (GRAs) in drug design are here summarized. Galectins, in particular, Gal‐1 and Gal‐3 are ubiquitous and important to biological systems, whose interactions with viral glycans modulate host immunity and homeostatic balance.

Seasonal effects decouple SARS-CoV-2 haplotypes worldwide

“…The role of the galectin-like fold of the NTD region of the S-protein is particularly significant. Both the NTD and RBD regions recognize and bind to sugars and other host cell receptors, enabling viral attachment and infection ( Pourrajab, 2021 ). They also present N- and O-linked glycosylation sites that act as a ‘glycan shield’ to camouflage the virus from host defenses.…”

“…Galectins are evolutionarily conserved glycan-binding effector proteins that regulate various processes, including cellular and extracellular interactions, pathogen recognition, and inflammation ( Dings et al , 2018 ). These roles involve binding to the carbohydrate moieties of glycoconjugates present on cell surfaces, reducing endocytosis by forming lattices, and regulating immunity signals ( Pourrajab, 2021 ). Galectins can either facilitate or avoid infections of a wide range of pathogens ( Ayona et al ., 2020 ).…”

The emergence of SARS-CoV-2 variants of concern in Australia by haplotype coalescence reveals a continental link to COVID-19 seasonality

“…In fact, our research suggests that the seasonality of COVID-19 can be explained by the presence of a galectin-like structure in the NTP region of the S1 subunit of the spike protein ( Caetano-Anollés et al, 2021 ). The NTD, together with the RBD region, facilitates the viral attachment to cells by recognizing and binding to sugars and other receptors of the host cell ( Pourrajab, 2021 ). Galectins are a family of evolutionarily conserved effector proteins that regulate a wide range of biological processes including pre-mRNA splicing and various kinds of cellular interactions, as well as pathogen recognition and inflammatory responses ( Dings, Miller, Griffin, & Mayo, 2018 ).…”

“…These diverse roles appear to mostly involve binding to the carbohydrate moieties of glycoconjugates present on the surface of cells ( Caetano-Anollés et al, 2021 ). The presence of cellular structures similar to galectins in the viral spike protein suggests they play a role in helping SARS-CoV-2 attach to host cells by using the same carbohydrate receptors used by galectins when evading host immune responses (possibly by masking itself from host galectins; Pourrajab, 2021 ). Such hypotheses about the role of these galectin like structures in SARS-CoV-2 have been corroborated by findings on the administration of SARS-Cov-2 galectin like inhibitors, which reportedly decrease SARS-CoV-2 loads in patients ( Sethi, Sanam, Munagalasetty, Jayanthi, & Alvala, 2020 ).…”

Dual role of Glycoconjugates and Binding Receptors in pathogenesis of Enveloped Viruses (by main focusing on two recent pandemics)

“…It interacts with host immune receptors via its glycotopes such as sialic acid and mannose moieties of glycoconjugates. The host immune receptors that recognise these moieties (PAMPs) as SAMPs include host Siglec-1, MBR and DC-SIGN. By binding to SAMP receptors, the virus simply enters the cell through endocytosis and is amplified by the cell endoplasmic reticulum pathway. Consequently, the virus modulates the host immune system activity in favour of its survival and dissemination, hypothetically immune suppression. SAMP receptors are mainly expressed by DCs and Mf localised at mucous present in skin, lung and epithelial interfaces. They act as the primary participants in cis-infection and trans-infection of virus-susceptible cells. Via glycotope receptors, highly pathogenic viruses invade host multiple organs and lead to systemic infection. Collectively, these findings identify a lectin-dependent pathway that enhances receptor-dependent infection by enveloped viruses and reveals distinct mechanisms of evading and suppressing the immune system (Refs 10–12). Finally, for the therapeutic purposes or prevention of viral infection, we should find general glycomimetic ligands or lectins that block the virus interaction with lectin receptors (Refs 12,13,89).…”