Inhibition of SARS-CoV-2 3CL Mpro by Natural and Synthetic Inhibitors: Potential Implication for Vaccine Production Against COVID-19

Ullah, Atta; Ullah, Kifayat

doi:10.3389/fmolb.2021.640819

Cited by 8 publications

(7 citation statements)

References 74 publications

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“…Suramin is an antiparasitic drug approved for the prophylactic treatment of sleeping sickness (trypanosomiasis) and river blindness (onchocerciasis) and has diverse antiviral properties . Its potential for treating SARS-CoV-2 has been reported, with evidence suggesting that it can block viral entry, ACE2 binding, and viral replication via inhibition of the RNA polymerase RdRp , and proteolytic processing by the 3CL protease Mpro . These reports corroborate our findings that suramin can block S protein binding to ACE2 and viral entry.…”

Section: Discussionsupporting

confidence: 89%

“…34 Its potential for treating SARS-CoV-2 has been reported, with evidence suggesting that it can block viral entry, 29 ACE2 binding, 11 and viral replication via inhibition of the RNA polymerase RdRp 34,35 and proteolytic processing by the 3CL protease Mpro. 36 These reports corroborate our findings that suramin can block S protein binding to ACE2 and viral entry. Two recent reports using commercially available kits reached different conclusions about the potency of suramin compared to our findings.…”

Section: ■ Discussionmentioning

confidence: 99%

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High-Throughput Assay for Identifying Diverse Antagonists of the Binding Interaction between the ACE2 Receptor and the Dynamic Spike Proteins of SARS-CoV-2

et al. 2022

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SARS-CoV-2, a coronavirus strain that started a worldwide pandemic in early 2020, attaches to human cells by binding its spike (S) glycoprotein to a host receptor protein angiotensin-converting enzyme 2 (ACE2). Blocking the interaction between the S protein and ACE2 has emerged as an important strategy for preventing viral infection. We systematically developed and optimized an AlphaLISA assay to investigate binding events between ACE2 and the ectodomain of the SARS-CoV-2 S protein (S-614G: residues 1–1208 with a D614G mutation). Using S-614G permits discovering potential allosteric inhibitors that stabilize the S protein in a conformation that impedes its access to ACE2. Over 30,000 small molecules were screened in a high-throughput format for activity against S-614G and ACE2 binding using the AlphaLISA assay. A viral entry assay was used to validate hits using lentiviral particles pseudotyped with the full-length S protein of the Wuhan-1 strain. Two compounds identified in the screen, oleic acid and suramin, blocked the attachment of S-614G to ACE2 and S protein-driven cell entry into Calu-3 and ACE2-overexpressing HEK293T cells. Oleic acid inhibits S-614G binding to ACE2 far more potently than to the receptor-binding domain (RBD, residues 319–541 of SARS-CoV-2 S), potentially indicating a noncompetitive mechanism. The results indicate that using the full-length ectodomain of the S protein can be important for identifying allosteric inhibitors of ACE2 binding. The approach reported here represents a rapidly adaptable format for discovering receptor-binding inhibitors to S-proteins of future coronavirus strains.

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Section: Discussionsupporting

confidence: 89%

Section: ■ Discussionmentioning

confidence: 99%

High-Throughput Assay for Identifying Diverse Antagonists of the Binding Interaction between the ACE2 Receptor and the Dynamic Spike Proteins of SARS-CoV-2

et al. 2022

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“…Suramin is an antiparasitic drug approved for the prophylactic treatment of sleeping sickness (trypanosomiasis) and river blindness (onchocerciasis) and has diverse antiviral properties. 32 Its potential for treating SARS-CoV-2 has been reported, with evidence suggesting that it can block viral entry 29 and ACE2 binding 11 , and viral replication via inhibition of the RNA polymerase RdRp 32,33 and proteolytic processing by the 3CL protease Mpro 34 . These reports corroborate our findings that suramin can block S protein binding to ACE2 and viral entry.…”

Section: Discussionmentioning

confidence: 99%

A high-throughput assay for identifying diverse antagonists of the binding interaction between the ACE2 receptor and the dynamic spike proteins of SARS-CoV-2

Sammons

Bohanon

Kowtha

et al. 2022

Preprint

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SARS-CoV-2, a coronavirus strain that started a worldwide pandemic in early 2020, attaches to human cells by binding its spike (S) glycoprotein to a host receptor protein angiotensin-converting enzyme 2 (ACE2). Blocking the interaction between the S protein and ACE2 has emerged as an important strategy for preventing viral infection. We systematically developed and optimized an AlphaLISA assay to investigate binding events between ACE2 and the ectodomain of the SARS-CoV-2 S protein (S-614G: residues 1–1208 with a D614G mutation). Using S-614G permits discovering potential allosteric inhibitors that stabilize the S protein in a conformation that impedes its access to ACE2. Over 30,000 small molecules were screened in a high-throughput format for activity against S-614G and ACE2 binding using the AlphaLISA assay. A viral entry assay was used to validate hits using lentiviral particles pseudotyped with the full-length S protein of the Wuhan-1 strain. Two compounds identified in the screen, oleic acid and suramin, blocked the attachment of S-614G to ACE2 and S protein-driven cell entry into Calu-3 and ACE2-overexpressing HEK293T cells. Oleic acid inhibits S-614G binding to ACE2 far more potently than to the receptor-binding domain (RBD, residues 319–541 of SARS-CoV-2 S), potentially indicating a non-competitive mechanism. The results indicate that using the full-length ectodomain of the S protein can be important for identifying allosteric inhibitors of ACE2 binding. The approach reported here represents a rapidly adaptable format for discovering receptor binding inhibitors to S-proteins of future coronavirus strains.

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“…The 2S albumin seed storage proteins (Ullah et al, 2015) and flocculating protein (Sousa et al, 2020) from M. oleifera are highly positively charged proteins. In our previous study, we had shown that these proteins bind to SARS-CoV-2 3CL M pro in-between domain II and III and restrict their moment (Ullah and Ullah, 2021). This may result in the inactivation of this enzyme.…”

Section: Differences Between Exfoliative Toxins and Other Serine Prot...mentioning

confidence: 97%

Three-Dimensional Structure Characterization and Inhibition Study of Exfoliative Toxin D From Staphylococcus aureus

et al. 2022

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The Staphylococcus aureus exfoliative toxins (ETs) are the main toxins that produce staphylococcal scalded skin syndrome (SSSS), an abscess skin disorder. The victims of the disease are usually newborns and kids, as well as grown-up people. Five ETs namely, exfoliative toxins A, B, C, D, and E have been identified in S. aureus. The three-dimensional (3D) structure of exfoliative toxins A, B, C and E is known, while that of exfoliative toxin D (ETD) is still unknown. In this work, we have predicted the 3D structure of ETD using protein modeling techniques (software used for 3D structure modeling comprising the MODELLER 9v19 program, SWISS-Model, and I-TESSER). The validation of the build model was done using PROCHECK (Ramachandran plot), ERRAT2, and Verify 3D programs. The results from 3D modeling show that the build model was of good quality as indicated by a GMQE score of 0.88 and by 91.1% amino acid residues in the most favored region of the Ramachandran plot, the ERRAT2 quality factor of 90.1%, and a verify3D score of >0.2 for 99.59% of amino acid residues. The 3D structure analysis indicates that the overall structure of ETD is similar to the chymotrypsin-like serine protease fold. The structure is composed of 13 β-strands and seven α-helices that fold into two well-defined six-strand β-barrels whose axes are roughly perpendicular to each other. The active site residues include histidine-97, aspartic acid-147, and serine-221. This represents the first structure report of ETD. Structural comparison with the other ETs shows some differences, particularly in the loop region, which also change the overall surface charge of these toxins. This may convey variable substrate specificity to these toxins. The inhibition of these toxins by natural (2S albumin and flocculating proteins from Moringa oleifera seeds) and synthetic inhibitors (suramin) was also carried out in this study. The results from docking indicate that the inhibitors bind near the C-terminal domain which may restrict the movement of this domain and may halt the access of the substrate to the active site of this enzyme. Molecular dynamic simulation was performed to see the effect of inhibitor binding to the enzyme. This work will further elucidate the structure–function relationship of this enzyme. The inhibition of this enzyme will lead to a new treatment for SSSS.

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Inhibition of SARS-CoV-2 3CL Mpro by Natural and Synthetic Inhibitors: Potential Implication for Vaccine Production Against COVID-19

Cited by 8 publications

References 74 publications

High-Throughput Assay for Identifying Diverse Antagonists of the Binding Interaction between the ACE2 Receptor and the Dynamic Spike Proteins of SARS-CoV-2

High-Throughput Assay for Identifying Diverse Antagonists of the Binding Interaction between the ACE2 Receptor and the Dynamic Spike Proteins of SARS-CoV-2

A high-throughput assay for identifying diverse antagonists of the binding interaction between the ACE2 receptor and the dynamic spike proteins of SARS-CoV-2

Three-Dimensional Structure Characterization and Inhibition Study of Exfoliative Toxin D From Staphylococcus aureus

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