Abstract
A modified form of heparan sulfate (HS) known as 3-O-sulfated heparan sulfate (3-OS HS) generates fusion receptor for herpes simplex virus (HSV) entry and spread. Primary cultures of corneal fibroblasts derived from human eye donors have shown the clinical significance of this receptor during HSV corneal infection. 3-OS HS- is a product of a rare enzymatic modification at C3 position of glucosamine residue which is catalyzed by 3-O-sulfotransferases (3-OSTs) enzymes. From humans to zebrafish, the 3-OST enzymes are highly conserved and widely expressed in cells and tissues. There are multiple forms of 3-OSTs each producing unique subset of sulfated HS making it chemically diverse and heterogeneous. HSV infection of cells or zebrafish can be used as a unique tool to understand the structural-functional activities of HS and 3-OS HS and likewise, the infection can be used as a functional assay to screen phage display libraries for identifying HS and 3-OS HS binding peptides or small molecule inhibitors. Using this approach over 200 unique 12-mer HS and 3-OS HS recognizing peptides were isolated and characterized against HSV corneal infection where 3-OS HS is known to be a key receptor. In this review we discuss emerging role of 3-OS HS based therapeutic strategies in preventing viral infection and tissue damage.
Highlights
Heparan sulfate (HS) glycosaminoglycans are hybrid molecules with unbranched polysaccharide polymers covalently attached to the protein core [1,2,3]
herpes simplex virus (HSV)-1 entry inhibitors generated against HS and 3-OST modified HS by our group, may turn useful to study HSV-1 induced pathological damages especially during ocular corneal infection or neuronal damages along with recurrent infections in zebrafish model because HS and 3-O-sulfated heparan sulfate (3-OS HS) have been widely implicated for their role in assisting HSV-1 entry and spread in both ocular and neuronal cells
In addition using mouse corneal model of HSV infection we further demonstrated the efficacy of the peptides in blocking infection in vivo, but it shows that HS is an important HSV-1 coreceptor, for cultured cells and for the cells in vivo [30]
Summary
Heparan sulfate (HS) glycosaminoglycans are hybrid molecules with unbranched polysaccharide polymers covalently attached to the protein core [1,2,3]. The synthesized chains are modified heterogeneously, and in domains, by multiple enzymes [4,5] Most common among these modifications is the addition of sulfate groups at various positions within the chain, which leads to the generation of specific motifs, making HS highly attractive for microbial adherence [6,7,8]. This structural diversity which is usually concentrated in the area of sulfation enables specific binding sites for >400 proteins, including cell adhesion molecules, growth factors, chemokines, and factors regulating angiogenesis and blood coagulation [9,10,11,12]. Various types of sulfation in HS chain are known to play critical role in viral entry, virus trafficking, and replication (Table 1). 3-OS HS plays a role in hepatitis B virus replication [46], while 6-O in HS chain potentially supports entry of cytomegalovirus [47]
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