In silico Analysis Revealed Potential Anti-SARS-CoV-2 Main Protease Activity by the Zonulin Inhibitor Larazotide Acetate

Abstract

The most severe outcome of COVID-19 infection is the development of interstitial pneumonia causing acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS), both responsible for the infected patients' mortality. ALI and ARDS are characterized by a leakage of plasma components into the lungs, compromising their ability to expand and optimally engage in gas exchange with blood, resulting in respiratory failure. We have previously reported that zonulin, a protein dictating epithelial and endothelial permeability in several districts, including the airways, is involved in ALI pathogenesis in mouse models, and that its peptide inhibitor Larazotide acetate (also called AT1001) ameliorated ALI and subsequent mortality by decreasing mucosal permeability to fluid and extravasation of neutrophils into the lungs. With the recent crystallographic resolution of the SARS-CoV-2 main protease (Mpro), an enzyme fundamental in the viral lifecycle, bound to peptidomimetic inhibitors N3 and 13b, we were able to perform molecular modeling investigation showing that AT1001 presents structural motifs similar to co-crystallized ligands. Specifically, molecular docking, MM-GBSA-based predictions and molecular dynamics showed that AT1001 docks extremely well in the Mpro catalytic domain through a global turn conformational arrangement without any unfavorable steric hindrance. Finally, we have observed that AT1001 can be superimposed onto the crystallized structures of N3 and 13b, establishing a higher number of interactions and accordingly a tighter binding. In vitro studies confirmed AT1001 anti-Mpro and preliminary investigation indicted an anti-viral activity. Combined, these studies suggest that AT1001, besides its well-demonstrated effect in ameliorating mucosal permeability in ALI/ARDS, may also exert a direct anti-SARS-CoV-2 effect by blocking the Mpro. AT1001 has been used extensively in a variety of animal models of ALI demonstrating robust safety and efficacy; it is currently in phase 3 trials in celiac subjects showing strong safety and efficacy profiles. We therefore propose its use as a specific anti-SARS-CoV-2 multitargeting treatment for the current pandemic.

Neurological Symptoms of COVID-19: The Zonulin Hypothesis

“…Furthermore, to label zonulin as one of the factors responsible for destroying or disrupting the BBB is crucial in order to find a possible therapy directed against the neurological manifestations that occur in COVID-19 patients. In fact, the already mentioned zonulin peptide antagonist, AT-1001, has been proposed as a specific anti-SARS-CoV-2 drug (27).…”

Targeting SARS-CoV-2 main protease by teicoplanin: A mechanistic insight by docking, MM/GBSA and molecular dynamics simulation

“… S.No. Compound a MM/GBSA binding energies (Kcal/mol) References 1 Lithospermic acid B −118.7 [49] 2 Ritonavir −107.6 [50] 3 AT1001 −106.3 [53] 4 GHRP-2 –106.0 [54] 5 Rutin −99.8 [51] 6 N3 −80.0 [55] 7 ChemDiv_D658-0159 −77.5 [56] 8 Amikacin −73.8 [52] 9 γ-glutamyl-S-allylcysteine −72.5 [57] 10 ZINC000003947429 −70.4 [58] 11 PubChem-129-716-607 −69.0 [59] 12 11b −65.6 [60] a Compound name has been kept same as reported in respective literature. …”

Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes)

“…Furthermore, the computational docking results revealed that several known and newly synthesized chemical compounds had high inhibitory binding affinities with the docked SARS-CoV-2 proteins, suggesting that they could be useful lead compounds for the design and synthesis of new anti-COVID-19 agents [ 304 , 309 , 310 ]. A combination of in silico analysis of immune system protein interactome networks, single-cell RNA sequencing of human tissues, and artificial neural networks was undertaken in one of the recent (2021) studies to reveal potential therapeutic targets for drug repurposing against COVID-19 [ 297 ].…”