In silico Design of Glyco-D,L-Peptide Antiviral Molecules

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.