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.

Keywords: coronavirus; glycan-recognition agents; glycans; spike protein.

FIGURE 1

The predicted structures of the spike glycoprotein (SGP) S in coronaviruses (SARS‐CoV, MERS‐CoV, SARS‐CoV‐2 (A‐D)), and the glycosylation profiles of detected N‐linked glycans (B‐D). The SGP S structure can be divided into the S1 and S2 domains, and the structural domains in the spike protein are located in the order (from C to the N terminus) as: transmembrane (TM), heptad repeats (HRs) in the S2 domain, C‐terminal domain (CTD), and N‐terminal domain (NTD) in the S1 domain as well as the signal peptide (SP). The S1‐CTD is divided into three subdomains SD‐SB, while S1‐NTD contains subdomain SA. SD‐SA is accounted as receptor‐binding domain (RBD). (B‐D) Glycosylation sites for oligomannose, hybrid and complex‐type N‐glycans are coloured in green, blue and red, respectively. Unique glycosylation sites for SARS‐CoV‐2 are dashed in violet, green and blue, the dual recognition of gangliosides and angiotensin‐converting enzyme‐2 (ACE‐ 2) by SARS‐CoV‐2 spike (S) protein. The viral protein displays two distinct domains, the tips of which are available for distinct types of interactions (S1‐NTD). The receptor‐binding domain (S1‐CTD) binds to the ACE‐2 receptor, and the N‐terminal domain (NTD) binds to the ganglioside/sialoglycan‐rich domain of the plasma membrane. Lipid rafts, which are membrane domains enriched in gangliosides and cholesterol, provide a perfect attractive interface for adequately positioning the viral S protein at the first step of the infection process

FIGURE 2

A, Amino acid sequence alignments of the ganglioside‐binding domain (GBD) of the SARS‐CoV‐2 spike protein (the reference sequence 6VSB‐A, fragment 97‐165) with clinical SARS‐CoV‐2 and Bat SARS‐like isolates (Deletions are highlighted in grey, amino acid changes in residues involved in ganglioside binding are highlighted in blue, conserved residues of GBD are lighted in red, and asparagine residues acting as glycosylation sites are highlighted in green) Structural and molecular modelling showed that amino acid residues 111‐162 of the N‐terminal domain (NTD) form a functional GBD, the interaction of which with lipid rafts can be efficiently prevented by chloroquine and hydroxychloroquine. B, Structural features of the SARS‐CoV‐2, MERS‐CoV and SARS‐CoV spike (S) proteins where the NTD could belong to a potential ganglioside‐binding domain. S1‐CTD: C‐ terminus of S1domain

FIGURE 3

Engagement of innate immune receptors causes phagocytosis and engulfment of the virus which facilitates and/or augments infection, independently of peptidase receptors. Virus engulfment by phagocyte cells and innate immune infection through C‐type lectins. A, Virus binding and infecting an erythrocyte through gangliosides/sialogylcans on the erythrocyte, 1) Erythrocyte infection leads to changes in the glycoprofile and influences 2 & 3) phagocytosis of the infected cells, through 3) the asialoglycoprotein receptors (sialic acid‐specific lectins) located on the spleen and liver phagocytes. 2) Virus lipid membrane exposes sialyl lactose moieties for Dendritic cell (DC)/Macrophage receptors (DC‐SIGN/Siglec‐1 via recognition of the viral envelope glycoprotein and viral membrane gangliosides). 4) Viral capture is followed by 5) accumulation in a storage compartment until 6) virus is released 7) to infect a contacting CD4+ T cell via viral envelope glycoprotein and CD4/co‐receptor interactions. Immune activating signals can induce Siglec‐1 expression and contribute to virus trans‐infection. DC, Dendritic cell; ICAM‐3, specific intercellular adhesion molecule 3; DC‐SIGN, grabbing non‐integrin; Siglecs, sialic acid‐binding immunoglobulin‐like lectins

FIGURE 4

Molecular and cellular interactions of chloroquine (CLQ) and hydroxychloroquine (CLQ‐OH) with different targets that inhibit virus entrance and expansion. Dual recognition of gangliosides and sialoglycans by CoV spike (S) protein is inhibited, by masking the sialoglycans and by interfering with receptor glycosylation, the interaction between cellular lipid rafts and viral envelop is efficiently prevented

FIGURE 5

Scheme of galectin‐3 (Gal‐3) and its oligomers when interacting with glycans, as its most important cellular functions in alveolar environments and the presence of the virus. Galectin‐3 recognizes and binds terminal sialo‐lactose or sub‐terminal galactose residues (preferentially recognize α2‐3‐sialylated N‐acetyllactosamines) (A) on viral spike glycoproteins or (B) epithelial cell surfaces. Galectins function in the opposite direction, (C) acting to reduce endocytosis of the cell surface pathogens by forming lattices, and (D) being more important in regulating the immunity signalling, as shown by T cells