The Symmetry of Viral Sialic Acid Binding Sites–Implications for Antiviral Strategies

Abstract

Virus infections are initiated by the attachment of the viral particle to protein or carbohydrate receptors on the host cell. Sialic acid-bearing glycan structures are prominently displayed at the cell surface, and, consequently, these structures can function as receptors for a large number of diverse viruses. Structural biology research has helped to establish the molecular bases for many virus–sialic acid interactions. Due to the icosahedral 532 point group symmetry that underlies many viral capsids, the receptor binding sites are frequently arranged in a highly symmetric fashion and linked by five-fold, three-fold, or two-fold rotation axes. For the inhibition of viral attachment, one emerging strategy is based on developing multivalent sialic acid-based inhibitors that can simultaneously engage several of these binding sites, thus binding viral capsids with high avidity. In this review, we will evaluate the structures of non-enveloped virus capsid proteins bound to sialylated glycan receptors and discuss the potential of these structures for the development of potent antiviral attachment inhibitors.

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

“…Herein, the S1B subdomain has a major influence on the virus‐host range and tissue tropism, and its receptor tissue localization varies between species 1,2,5,25 . Whereas, the S1A subdomain which participating in the early phase of viral attachment and infection shares conserved structural folds and sugar‐binding sites in different viral lectins 4,5,24,25 …”

“…Glycans function as early attachment receptors to simply tether a virus to the target cell membrane that is followed by the recruitment of secondary (co‐)receptors and endocytosis factors, as well as, the delivery of the viral genome into the cytoplasm 4 …”

“…Among the enveloped viruses that recognize Sia‐containing receptors are members of the families Coronaviridae, Paramyxoviridae and Orthomyxoviridae 4 . CoV GPSs share structural features in their sugar‐binding sites (S1‐NTD) resembling the galectin‐3 folding structure in humans 24 .…”

“…Examples of differences between tissues in the same host can be found in human airways and eyes, where Sia is usually linked to other sugars via α2,6‐glycosidic and α2,3‐glycosidic bonds, respectively. Or, there are differences in Sia distribution between the human upper and lower respiratory tract, where mainly expresses α2,6‐linked and α2,3‐linked Sia, respectively 4,37,43 . There are differences in the Sia biology between humans and apes, where the expression of Sia α2,3/6‐glycosidic bonds on the airway epithelium is human‐specific and absent in the apes.…”

“…It is an important determinant of viral host range and cross‐species infection and a primary target for antiviral intervention. Coronaviruses recognize a variety of host receptors (including protein or carbohydrate receptors) through the spike protein, infect many hosts and are health threats to humans and animals 1‐4 …”