Abstract
Heparan sulfate (HS) and its highly modified form, 3-O-sulfated heparan sulfate (3-OS HS), contribute strongly to herpes simplex virus type-1 (HSV-1) infection in vitro. Here we report results from a random M13-phage display library screening to isolate 12-mer peptides that bind specifically to HS, 3-OS HS, and block HSV-1 entry. The screening identified representative candidates from two-different groups of anti-HS peptides with high positive charge densities. Group 1, represented by G1 peptide (LRSRTKIIRIRH), belongs to a class with alternating charges (XRXRXKXXRXRX), and group 2, represented by G2 peptide (MPRRRRIRRRQK), shows repetitive charges (XXRRRRXRRRXK). Viral entry and glycoprotein D binding assays together with fluorescent microscopy data indicated that both G1 and G2 were potent in blocking HSV-1 entry into primary cultures of human corneal fibroblasts and CHO-K1 cells transiently expressing different glycoprotein D receptors. Interestingly, G2 peptide isolated against 3-OS HS displayed wider ability to inhibit entry of clinically relevant strains of HSV-1 and some divergent members of herpesvirus family including cytomegalovirus and human herpesvirus-8. To identify functional residues within G1 and G2, we performed point mutations and alanine-scanning mutagenesis. Several arginine and a lysine residues were needed for anti-HSV-1 activity, suggesting the importance of the positively charged residues in virus-cell binding and virus-induced membrane fusion. In vivo administration of G1 or G2 peptide as a prophylactic eye drop completely blocked HSV-1 spread in the mouse cornea as evident by immunohistochemistry. This result also highlights an in vivo significance of HS and 3-OS HS during ocular herpes infection.
Highlights
Heparan sulfate (HS)2 moieties present on cell surfaces provide attachment sites for many human and non-human patho
HS expressed on spermatozoa plays a key role in the capture of human immunodeficiency virus (HIV) and its transmission to dendritic, macrophage, and T cells [19]. 3-O-sulfated heparan sulfate (3-OS HS) plays a role in hepatitis B virus replication [20] and HS-binding peptides, or compounds can be successfully used for preventing genital human papilloma virus, HIV, and cytomegalovirus infection [21,22,23,24]
We found that the peptides function by interfering with the binding of herpes simplex virus type-1 (HSV-1) to cells
Summary
Heparan sulfate (HS)2 moieties present on cell surfaces provide attachment sites for many human and non-human patho-. We report results from a random M13-phage display library screening to isolate 12-mer peptides that bind to HS, 3-OS HS, and block HSV-1 entry. Viral entry and glycoprotein D binding assays together with fluorescent microscopy data indicated that both G1 and G2 were potent in blocking HSV-1 entry into primary cultures of human corneal fibroblasts and CHO-K1 cells transiently expressing different glycoprotein D receptors.
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