Peptides as Therapeutic Agents for Dengue Virus

Chew, Miaw-Fang; Poh, Keat-Seong; Poh, Chit-Laa

Another important known DENV receptor is the glycosaminoglycans (GAG). Among the GAG family, heparin sulfate (HS) is the most ubiquitous member of the family and is the putative receptor for DENV [92] [93] [94] . Studies have shown that HS acted as the first interactive attachment factor to facilitate DENV binding to the second receptor [92, 95] . It was demonstrated that DENV-HS interacted via positively charged E(III) residues, especially Lys291 and Lys 295 binding to the negatively charged HS [73, 96] . Many heparan mimetics were identified to block DENV infection [79, 80, 97] . Lee et al. (2006) showed that a heparin sulfate mimetic, phosphomannopentaose sulfate (PI-88), significantly increased the survival rate of DENV-infected mice [79] . In another study, a sulphated polysaccharide, fucoidan, which was extracted from the marine alga Cladosiphon, was able to inhibit DENV-2 infection by binding to the DENV envelope protein [80] . Interestingly, Talarico et al. (2005) showed that iota-carrageenan and dl-galactan hybrid C2S-3 (sulphated polysaccharides isolated from the red seaweeds Gymnogongrus griffithsiae and Cryptonemia crenulata) inhibited DENV infection in a virus serotype and host cell dependent manner [97] . Many other heparin mimetics, including CF-238 [81] , sulphated galactomannan [98] , curdlan sulfate [99] , sulphated galactan [98] , sulphated K5 [100] and chondroitin sulfate [101] , were found to inhibit DENV infection but no antiviral peptide was identified to either bind to cellular receptor or act as a receptor mimetic to block DENV entry thus far. Likewise, to the best of our knowledge, no antiviral peptide was found to inhibit DENV infection by targeting other receptors, including mannose receptor [74] , HSP 90/70 [75] , laminin receptor [76] , and the TIM and TAM proteins [77] . Furthermore, inhibitors targeting host cellular receptor(s) are anticipated to be less prone to develop resistance as compared to those targeting viruses. Therefore, this may serve as an interesting research gap to be explored.