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. 2023 Sep 13;8(38):35207-35218.
doi: 10.1021/acsomega.3c04903. eCollection 2023 Sep 26.

Therapeutic Potential of Antiviral Peptides against the NS2B/NS3 Protease of Zika Virus

Md Shahadat Hossain  1 , Md Tanjil Islam Shovon  1 , Md Rafid Hasan  1 , Fuad Taufiqul Hakim  1 , Mohammad Mehedi Hasan  1 , Sadia Afrose Esha  1 , Sabiha Tasnim  1 , Md Shahoriar Nazir  1 , Fahmida Akhter  1 , Md Ackas Ali  2 , Mohammad A Halim  2
Affiliations

Therapeutic Potential of Antiviral Peptides against the NS2B/NS3 Protease of Zika Virus

Md Shahadat Hossain et al. ACS Omega. .

Abstract

The NS2B/NS3 protease is highly conserved among various proteases of the Zika virus, making it an important therapeutic target for developing broad-spectrum antiviral drugs. The NS2B/NS3 protease is a crucial enzyme in the replication cycle of Zika virus and plays a significant role in viral maturation and assembly. Inhibiting the activity of this protease can potentially prevent viral replication, making it an attractive target for developing therapies against Zika virus infection. This work screens 429 antiviral peptides in comparison with substrate peptide against the NS2B/NS3 of Zika virus using molecular docking and molecular dynamics (MD) simulation. Based on the docking screening, MD simulation conducted for the best four peptides including AVP0239, AVP0642, AVP0660, and AVP2044, could be effective against NS2B/NS3. These results were compared with the control substrate peptide. Further analysis indicates that AVP0642 and AVP2044 are the most promising candidates. The interaction analysis showed that the catalytic site residues including His51, Asp75, Ser135 and other non-catalytic residues such as Asp129, Asp83, and Asp79 contribute substantial interactions. Hydrogen bonds (41%) and hydrophobic interactions (33%) are observed as the prominent non-covalent interaction prompting the peptide-protein complex formation. Furthermore, the structure-activity relationship (SAR) illustrates that positively charged (Lys, Arg) residues in the peptides dominate the interactions. This study provides the basis for developing novel peptide-based protease inhibitors for Zika virus.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Molecular dynamics simulation. (A) Root-mean squared deviation (RMSD); (B) radius of gyration (Rg); (C) solvent-accessible surface area (SASA); (D) root-mean-squared fluctuation (RMSF); (Sequence 1-37, NS2B and 38-185, NS3); (E) scores plot; and (F) loading plot of top four peptides–NS2B/NS3 complexes and a substrate peptide over 200 ns simulation.
Figure 2
Figure 2
Representative snapshots with RMSD. NS2B/NS3 (Middle Blue Green); (A) NS2B/NS3–substrate peptide; (B) NS2B/NS3–AVP0642; (C) NS2B/NS3–AVP2044; (D) NS2B/NS3–AVP0660; (E) NS2B/NS3–AVP0239; over 200 ns MD simulation.
Figure 3
Figure 3
Binding free energy distribution of complexes in kcal/mol. (A) NS2B/NS3–AVP0642; (B) NS2B/NS3–AVP2044; (C) NS2B/NS3–AVP0660; (D) NS2B/NS3–AVP0239; (E) NS2B/NS3–substrate peptide; (F) comparison of binding free of last 100 ns simulation snapshots.
Figure 4
Figure 4
Peptide–protein interaction closeview. (A) NS2B/NS3–substrate peptide; (B) NS2B/NS3–AVP0642; (C) NS2B/NS3–AVP2044; (D) NS2B/NS3–AVP0660; (E) NS2B/NS3–AVP0239; of final snapshots at 200 ns.
Figure 5
Figure 5
NS2B/NS3–substrate peptide complex. (A) Interacting substrate peptide residues; (B) interacting NS2B/NS3 residues; (C) distribution of non-covalent interactions; over 200 ns MD simulation.
Figure 6
Figure 6
NS2B/NS3–AVP0642 complex. (A) Interacting AVP0642 residues; (B) interacting NS2B/NS3 residues; (C) distribution of non-covalent interactions; over 200 ns MD simulation.
Figure 7
Figure 7
Biplot of the selected 30 high binding affinity peptides clustered based on four peptide properties.
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