Sulfated Glycans and Related Digestive Enzymes in the Zika Virus Infectivity: Potential Mechanisms of Virus-Host Interaction and Perspectives in Drug Discovery

Abstract

As broadly reported, there is an ongoing Zika virus (ZIKV) outbreak in countries of Latin America. Recent findings have demonstrated that ZIKV causes severe defects on the neural development in fetuses in utero and newborns. Very little is known about the molecular mechanisms involved in the ZIKV infectivity. Potential therapeutic agents are also under investigation. In this report, the possible mechanisms of action played by glycosaminoglycans (GAGs) displayed at the surface proteoglycans of host cells, and likely in charge of interactions with surface proteins of the ZIKV, are highlighted. As is common for the most viruses, these sulfated glycans serve as receptors for virus attachment onto the host cells and consequential entry during infection. The applications of (1) exogenous sulfated glycans of different origins and chemical structures capable of competing with the virus attachment receptors (supposedly GAGs) and (2) GAG-degrading enzymes able to digest the virus attachment receptors on the cells may be therapeutically beneficial as anti-ZIKV. This communication attempts, therefore, to offer some guidance for the future research programs aimed to unveil the molecular mechanisms underlying the ZIKV infectivity and to develop therapeutics capable of decreasing the devastating consequences caused by ZIKV outbreak in the Americas.

Figure 1

Structural representation of (a) heparan sulfate (HS) and (b) chondroitin sulfate (CS) and subtypes. (a) The repeating disaccharide unit of HS is composed of alternating 4-linked uronic acid and 4-linked α-glucosamine (GlcNX) units. The uronic acid can be either β-d-glucuronic acid (GlcA) as its major component or α-l-glucuronic acid (IdoA). Regarding possible substitutions, the GlcNX units are frequently N-acetylated (GlcNAc), occasionally N-sulfated (GlcNS), and rarely N-free (just the amino NH₂ group, as GlcN). O-sulfation can occur at both units of HS. While 2-O-sulfation occurs occasionally at the IdoA, 6-O-sulfation is common at the GlcNS units. 3-O-sulfation may also occur at the occasional GlcNS6S unit but very rarely in terms of amounts. (b) The repeating disaccharide unit of CS is composed of alternating 4-linkedβ-d-glucuronic acid (GlcA) and 3-linked β-d-galactosamine (GalNAc) units. The CS subtypes differ according to sulfation patterns as follows: CS-A is mostly 4-O-sulfated at the GalNAc units, CS-C is predominantly 6-O-sulfated at the GalNAc units, CD-D is mostly 2-O-sulfated at the GlcA units and 6-O-sulfated at the GalNAc units, and CS-E is mostly 4,6-O-disulfated at the GalNAc units. In both panels, the glycosidic bonds are indicated inside the ellipses, whereas monosaccharide types are indicated inside the rectangles. For fast notation of the sulfation patterns, sulfation sites are highlighted by light-grey shadowed rectangles.