Abstract
Background: Most licensed antiviral drugs are nucleoside analogs. A recent research focuses on blocking a virus from entering the cells in the viral cell adsorption/entry stage. In this entry mechanism, the glycans present on the viral surface play a fundamental role. Homochiral L-peptides acting this fusion mechanism have shown some inhibition of viral infection. Peptides with regularly alternating enantiomeric sequence (L,D-peptides) can assume structures that are not accessible to the corresponding homochiral molecules. Furthermore, L,D-peptides are less sensitive to enzymatic digestion. Aim: In silico design of an L, D-peptide with a high affinity for the viral surface glycans and consequently able to interfere with its fusion mechanism. Methods: We used a [Formula: see text]-Mannopentaose (3-6MP) molecule to simulate a viral surface glycan. We performed molecular dynamics (MD) simulations of 3-6MP and D,L-peptide in water using the force field AMBER12-GLYCAM06i. We evaluated the binding constant from trajectories. The D,L-peptide molecule was modified over the sequence, the length, the terminals and finally glycosylated to attain a very high binding constant value for 3-6MP. In addition, we studied the specific interaction between T lymphocyte CD4 glycoprotein and HIV envelope glycoprotein gp120 through MD simulations between a D,L-peptide, bounded to a typical CD4 glycan, and a highly conserved HIV gp120 glycan. Results: Concerning the interaction with 3-6MP molecule, the very effective molecule obtained was H-d-Trp-l-Pro-d-Asn-l-Pro-d-Trp-l-Pro-d-Asn-l-Pro-OH where the Asn residues in position 3 and 7 are glycosylated with alpha-D-Mannopyranosyl-([Formula: see text])-[alpha-D-mannopyranosyl-([Formula: see text])]-alpha-D-mannopyranosyl-([Formula: see text])-N-acetyl-beta-D-glucopyranosyl-([Formula: see text])-N-acetyl-beta-D-glucopyranosyl-1-OH. As far as the interaction with HIV envelope is considered instead, the very effective molecule obtained, able to antagonize the CD4 glycoprotein, was H-d-Trp-l-Pro-d-Asn-l-Pro-d-Trp-l-Pro-d-Asn-l-Pro-OH where the Asn residue in position 3 is glycosylated with alpha-D-galactopyranosyl-([Formula: see text])- N-acetyl-beta-D-glucopyranosyl-([Formula: see text])-alpha-D-Mannopyranosyl-([Formula: see text])- [alpha-D-galactopyranosyl-([Formula: see text])- N-acetyl-beta-D-glucopyranosyl-([Formula: see text])- alpha-D-Mannopyranosyl-([Formula: see text])]- beta-D-mannopyranosyl-([Formula: see text])-N-acetyl-beta-D-glucopyranosyl-([Formula: see text])-N-acetyl-beta-D-glucopyranosyl-1-OH Conclusion: The above optimized glycosylated D,L-peptide molecules could be very promising representatives of a new powerful class of antiviral agents.
In silico design of glyco-D,L-peptides with high affinity for the viral surface glycans and consequently able to interfere with its fusion mechanism. Molecular Dynamics (MD) simulations are performed using the GROMACS suite and the force field AMBER12-GLYCAM06i. A very high binding is realized between: the glyco-D,L-peptide TrpProAsnPenta and the common viral surface glycan 3-6MP [1]; the glyco-D,L-peptide TrpProAsn9glyco and the conserved gp120 HIV glycan N262glyco [2].