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. 2021 Feb 26;13(3):307.
doi: 10.3390/pharmaceutics13030307.

Repurposing of Sitagliptin- Melittin Optimized Nanoformula against SARS-CoV-2: Antiviral Screening and Molecular Docking Studies

Mohammed W Al-Rabia  1 , Nabil A Alhakamy  2   3   4 , Osama A A Ahmed  2   3   4 , Khalid Eljaaly  5   6 , Ahmed L Alaofi  7 , Ahmed Mostafa  8 , Hani Z Asfour  1 , Ahmed A Aldarmahi  9 , Khaled M Darwish  10 , Tarek S Ibrahim  11 , Usama A Fahmy  2   3   4
Affiliations

Repurposing of Sitagliptin- Melittin Optimized Nanoformula against SARS-CoV-2: Antiviral Screening and Molecular Docking Studies

Mohammed W Al-Rabia et al. Pharmaceutics. .

Abstract

The outbreak of the COVID-19 pandemic in China has become an urgent health and economic challenge. The objective of the current work was to evaluate the efficacy of the combined complex of Sitagliptin (SIT) with melittin (MEL) against SARS-CoV-2 virus. SIT-MEL nano-conjugates were optimized by a full three-factor bi-level (23) factorial design. In addition, SIT concentration (mM, X1), MEL concentration (mM, X2), and pH (X3) were selected as the critical factors. Particle size (nm, Y1) and zeta potential (mV, Y2) were assessed as responses. Characterization of the optimized formula for Fourier-transformed infrared (FTIR) was carried out. The optimized formula showed particle size and zeta potential values of 77.42 nm and 27.67 mV, respectively. When compared with SIT and MEL, the combination of SIT-MEL complex has shown anti-viral potential against isolate of SARS-CoV-2 with IC50 values of 8.439 μM with significant improvement (p < 0.001). In addition, the complex showed IC50 in vitro 3CL-protease inhibition with IC50 7.216 µM. Molecular docking has revealed that formula components have good predicted pocket accommodation of the SARS-CoV-2 3-CL protease. An optimized formulation of SIT-MEL could guarantee both enhanced delivery to the target cells and the enhanced cellular uptake with promising activities against SARS-CoV-2.

Keywords: COVID-19; bee venom; nanoparticles; pandemic diseases.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Standardized Pareto chart for the (A) particle size and (B) zeta potential of SIT-MEL nano-sized systems.
Figure 2
Figure 2
Main effects of SIT concentration (X1), MEL concentration (X2), and pH (X3) on particle size of SIT-MEL nano-sized systems.
Figure 3
Figure 3
Main effects (A–C) and interactions (D–F) of SIT concentration (X1), MEL concentration (X2), and pH (X3) on zeta potential of SIT-MEL nano-sized systems.
Figure 4
Figure 4
FTIR spectra of SIT (A), MEL (B) and combination of SIT-MEL (C).
Figure 5
Figure 5
IC50 of SIT (A), MEL (B), and combination of SIT-MEL (C) against SARS-CoV-2.
Figure 6
Figure 6
Inhibition of 3CL Protease enzyme activity by SIT (A), MEL (B), SIT-MEL (C) and GC376 inhibitor control (D).
Figure 7
Figure 7
Structure of crystallized SARS-CoV-2 3CLpro target complex (PDB code: 6lu7). Protein target (gray surface) is bound to the crystallized potent irreversible inhibitor (N3; yellow sticks), within the canonical substrate binding site. This shows the four important sub-pockets (S1’, S1, S2, and S3, as red, magenta, orange, and blue color, respectively). Zoomed stereoview of N3 (yellow sticks represent the ligand–protein hydrogen bonding as black dashed-lines. Residues (lines) located within 5 Å radius of bound ligands are colored in accordance with sub-pocket being labeled with sequence numbers.
Figure 8
Figure 8
Docking poses sitagliptin (A); melittin formulation proteinomimetic ligand (B), within the SARS-CoV-2 3CLpro active site (PDB code: 6lu7). Left panels depict the suggested ligand-target complexes showing docked ligands as green sticks, while 3CLpro target (gray surface) with different colored sub-pockets (S1’ = red; S1 = magenta; S2 = orange; S3 = blue). Overlaid conformations of docked ligands (green sticks) and crystallized N3 (yellow sticks) are depicted at rights panels. The ligand–protein hydrogen interactions are represented as black dashed-lines. Residues (lines) located within 5 Å radius of bound ligands are colored in accordance with sub-pocket being labeled with sequence numbers.
Figure 9
Figure 9
Superimposed conformations of docking ligands within SARS-CoV-2 3CLpro main protease active site (PDB code: 6lu7). Docked ligands are shown as sticks 3D-representation (Melittin = green and sitagliptin = magenta) at the binding site of target protein (gray surface) representing different colored sub-pockets (S1’ = red; S1 = magenta; S2 = orange; S3 = blue).
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