Abstract
BackgroundGriffithsin, a 121-residue protein isolated from a red algal Griffithsia sp., binds high mannose N-linked glycans of virus surface glycoproteins with extremely high affinity, a property that allows it to prevent the entry of primary isolates and laboratory strains of T- and M-tropic HIV-1. We used the sequence of a portion of griffithsin's sequence as a design template to create smaller peptides with antiviral and carbohydrate-binding properties.Methodology/ResultsThe new peptides derived from a trio of homologous β-sheet repeats that comprise the motifs responsible for its biological activity. Our most active antiviral peptide, grifonin-1 (GRFN-1), had an EC50 of 190.8±11.0 nM in in vitro TZM-bl assays and an EC50 of 546.6±66.1 nM in p24gag antigen release assays. GRFN-1 showed considerable structural plasticity, assuming different conformations in solvents that differed in polarity and hydrophobicity. Higher concentrations of GRFN-1 formed oligomers, based on intermolecular β-sheet interactions. Like its parent protein, GRFN-1 bound viral glycoproteins gp41 and gp120 via the N-linked glycans on their surface.ConclusionIts substantial antiviral activity and low toxicity in vitro suggest that GRFN-1 and/or its derivatives may have therapeutic potential as topical and/or systemic agents directed against HIV-1.
Highlights
Preventing HIV-1 infection is the primary goal of pre- and postexposure prophylaxis of HIV
Its substantial antiviral activity and low toxicity in vitro suggest that GRFN-1 and/or its derivatives may have therapeutic potential as topical and/or systemic agents directed against HIV-1
Reduced peptides were purified by preparative reverse-phase high performance liquid chromatography (RP-HPLC) to .90% homogeneity and their purity evaluated by matrix-assisted laser desorption ionization spectrometry (MALDI-MS) and analytical RP-HPLC
Summary
Preventing HIV-1 infection is the primary goal of pre- and postexposure prophylaxis of HIV. Prophylactic modalities that block HIV-1 entry would be valuable, because latent HIV-1 infections are typically refractory to therapeutic or immunological interventions [1,2,3,4,5,6,7,8,9] Lectins, especially those targeting the high mannose, N-linked glycans of HIV surface glycoproteins [10], are exceptionally potent HIV entry inhibitors. Griffithsin, a 121-residue protein isolated from a red algal Griffithsia sp., binds high mannose N-linked glycans of virus surface glycoproteins with extremely high affinity, a property that allows it to prevent the entry of primary isolates and laboratory strains of T- and M-tropic HIV-1. We used the sequence of a portion of griffithsin’s sequence as a design template to create smaller peptides with antiviral and carbohydrate-binding properties
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