Identification of a dual acting SARS-CoV-2 proteases inhibitor through in silico design and step-by-step biological characterization
COVID-19 pandemic, starting from the latest 2019, and caused by SARS-CoV-2 pathogen, led to the hardest health-socio-economic disaster in the last century. Despite the tremendous scientific efforts, mainly focused on the development of vaccines, identification of potent and efficient anti-SARS-CoV-2...
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| Published in | European journal of medicinal chemistry Vol. 226; p. 113863 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
ISSY-LES-MOULINEAUX
Elsevier Masson SAS
15.12.2021
Elsevier |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0223-5234 1768-3254 1768-3254 |
| DOI | 10.1016/j.ejmech.2021.113863 |
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| Abstract | COVID-19 pandemic, starting from the latest 2019, and caused by SARS-CoV-2 pathogen, led to the hardest health-socio-economic disaster in the last century. Despite the tremendous scientific efforts, mainly focused on the development of vaccines, identification of potent and efficient anti-SARS-CoV-2 therapeutics still represents an unmet need. Remdesivir, an anti-Ebola drug selected from a repurposing campaign, is the only drug approved, so far, for the treatment of the infection. Nevertheless, WHO in later 2020 has recommended against its use in COVID-19. In the present paper, we describe a step-by-step in silico design of a small library of compounds as main protease (Mpro) inhibitors. All the molecules were screened by an enzymatic assay on Mpro and, then, cellular activity was evaluated using Vero cells viral infection model. The cellular screening disclosed compounds 29 and 34 as in-vitro SARS-CoV-2 replication inhibitors at non-toxic concentrations (0.32 < EC50 < 5.98 μM). To rationalize these results, additional in-vitro assays were performed, focusing on papain like protease (PLpro) and spike protein (SP) as potential targets for the synthesized molecules. This pharmacological workflow allowed the identification of compound 29, as a dual acting SARS-CoV-2 proteases inhibitor featuring micromolar inhibitory potency versus Mpro (IC50 = 1.72 μM) and submicromolar potency versus PLpro (IC50 = 0.67 μM), and of compound 34 as a selective SP inhibitor (IC50 = 3.26 μM).
[Display omitted]
•Indole based compounds were designed in-silico as SARS-CoV-2 main protease inhibitors.•Step-by-step optimization of the cognate compounds was performed by in-vitro assays.•Different compounds showed low μM potencies when challenged in SARS-CoV-2 transfected Vero cells.•Further investigations were performed over different SARS-CoV-2 targets.•A dual Mpro/PLpro inhibitor and a selective SP inhibitor were disclosed. |
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| AbstractList | COVID-19 pandemic, starting from the latest 2019, and caused by SARS-CoV-2 pathogen, led to the hardest health-socio-economic disaster in the last century. Despite the tremendous scientific efforts, mainly focused on the development of vaccines, identification of potent and efficient anti-SARS-CoV-2 therapeutics still represents an unmet need. Remdesivir, an anti-Ebola drug selected from a repurposing campaign, is the only drug approved, so far, for the treatment of the infection. Nevertheless, WHO in later 2020 has recommended against its use in COVID-19. In the present paper, we describe a step-by-step in silico design of a small library of compounds as main protease (M
) inhibitors. All the molecules were screened by an enzymatic assay on M
and, then, cellular activity was evaluated using Vero cells viral infection model. The cellular screening disclosed compounds 29 and 34 as in-vitro SARS-CoV-2 replication inhibitors at non-toxic concentrations (0.32 < EC
< 5.98 μM). To rationalize these results, additional in-vitro assays were performed, focusing on papain like protease (PL
) and spike protein (SP) as potential targets for the synthesized molecules. This pharmacological workflow allowed the identification of compound 29, as a dual acting SARS-CoV-2 proteases inhibitor featuring micromolar inhibitory potency versus M
(IC
= 1.72 μM) and submicromolar potency versus PL
(IC
= 0.67 μM), and of compound 34 as a selective SP inhibitor (IC
= 3.26 μM). COVID-19 pandemic, starting from the latest 2019, and caused by SARS-CoV-2 pathogen, led to the hardest health-socio-economic disaster in the last century. Despite the tremendous scientific efforts, mainly focused on the development of vaccines, identification of potent and efficient anti-SARS-CoV-2 therapeutics still represents an unmet need. Remdesivir, an anti-Ebola drug selected from a repurposing campaign, is the only drug approved, so far, for the treatment of the infection. Nevertheless, WHO in later 2020 has recommended against its use in COVID-19. In the present paper, we describe a step-by-step in silico design of a small library of compounds as main protease (Mpro) inhibitors. All the molecules were screened by an enzymatic assay on Mpro and, then, cellular activity was evaluated using Vero cells viral infection model. The cellular screening disclosed compounds 29 and 34 as in-vitro SARS-CoV-2 replication inhibitors at non-toxic concentrations (0.32 < EC50 < 5.98 μM). To rationalize these results, additional in-vitro assays were performed, focusing on papain like protease (PLpro) and spike protein (SP) as potential targets for the synthesized molecules. This pharmacological workflow allowed the identification of compound 29, as a dual acting SARS-CoV-2 proteases inhibitor featuring micromolar inhibitory potency versus Mpro (IC50 = 1.72 μM) and submicromolar potency versus PLpro (IC50 = 0.67 μM), and of compound 34 as a selective SP inhibitor (IC50 = 3.26 μM). [Display omitted] •Indole based compounds were designed in-silico as SARS-CoV-2 main protease inhibitors.•Step-by-step optimization of the cognate compounds was performed by in-vitro assays.•Different compounds showed low μM potencies when challenged in SARS-CoV-2 transfected Vero cells.•Further investigations were performed over different SARS-CoV-2 targets.•A dual Mpro/PLpro inhibitor and a selective SP inhibitor were disclosed. COVID-19 pandemic, starting from the latest 2019, and caused by SARS-CoV-2 pathogen, led to the hardest health-socio-economic disaster in the last century. Despite the tremendous scientific efforts, mainly focused on the development of vaccines, identification of potent and efficient anti-SARS-CoV-2 therapeutics still represents an unmet need. Remdesivir, an anti-Ebola drug selected from a repurposing campaign, is the only drug approved, so far, for the treatment of the infection. Nevertheless, WHO in later 2020 has recommended against its use in COVID-19. In the present paper, we describe a step-by-step in silico design of a small library of compounds as main protease (Mpro) inhibitors. All the molecules were screened by an enzymatic assay on Mpro and, then, cellular activity was evaluated using Vero cells viral infection model. The cellular screening disclosed compounds 29 and 34 as in-vitro SARS-CoV-2 replication inhibitors at non-toxic concentrations (0.32 < EC50 < 5.98 μM). To rationalize these results, additional in-vitro assays were performed, focusing on papain like protease (PLpro) and spike protein (SP) as potential targets for the synthesized molecules. This pharmacological workflow allowed the identification of compound 29, as a dual acting SARS-CoV-2 proteases inhibitor featuring micromolar inhibitory potency versus Mpro (IC50 = 1.72 μM) and submicromolar potency versus PLpro (IC50 = 0.67 μM), and of compound 34 as a selective SP inhibitor (IC50 = 3.26 μM).COVID-19 pandemic, starting from the latest 2019, and caused by SARS-CoV-2 pathogen, led to the hardest health-socio-economic disaster in the last century. Despite the tremendous scientific efforts, mainly focused on the development of vaccines, identification of potent and efficient anti-SARS-CoV-2 therapeutics still represents an unmet need. Remdesivir, an anti-Ebola drug selected from a repurposing campaign, is the only drug approved, so far, for the treatment of the infection. Nevertheless, WHO in later 2020 has recommended against its use in COVID-19. In the present paper, we describe a step-by-step in silico design of a small library of compounds as main protease (Mpro) inhibitors. All the molecules were screened by an enzymatic assay on Mpro and, then, cellular activity was evaluated using Vero cells viral infection model. The cellular screening disclosed compounds 29 and 34 as in-vitro SARS-CoV-2 replication inhibitors at non-toxic concentrations (0.32 < EC50 < 5.98 μM). To rationalize these results, additional in-vitro assays were performed, focusing on papain like protease (PLpro) and spike protein (SP) as potential targets for the synthesized molecules. This pharmacological workflow allowed the identification of compound 29, as a dual acting SARS-CoV-2 proteases inhibitor featuring micromolar inhibitory potency versus Mpro (IC50 = 1.72 μM) and submicromolar potency versus PLpro (IC50 = 0.67 μM), and of compound 34 as a selective SP inhibitor (IC50 = 3.26 μM). COVID-19 pandemic, starting from the latest 2019, and caused by SARS-CoV-2 pathogen, led to the hardest health-socio-economic disaster in the last century. Despite the tremendous scientific efforts, mainly focused on the development of vaccines, identification of potent and efficient anti-SARS-CoV-2 therapeutics still represents an unmet need. Remdesivir, an anti-Ebola drug selected from a repurposing campaign, is the only drug approved, so far, for the treatment of the infection. Nevertheless, WHO in later 2020 has recommended against its use in COVID-19. In the present paper, we describe a step-by-step in silico design of a small library of compounds as main protease (M pro ) inhibitors. All the molecules were screened by an enzymatic assay on M pro and, then, cellular activity was evaluated using Vero cells viral infection model. The cellular screening disclosed compounds 29 and 34 as in-vitro SARS-CoV-2 replication inhibitors at non-toxic concentrations (0.32 < EC 50 < 5.98 μM). To rationalize these results, additional in-vitro assays were performed, focusing on papain like protease (PL pro ) and spike protein (SP) as potential targets for the synthesized molecules. This pharmacological workflow allowed the identification of compound 29 , as a dual acting SARS-CoV-2 proteases inhibitor featuring micromolar inhibitory potency versus M pro (IC 50 = 1.72 μM) and submicromolar potency versus PL pro (IC 50 = 0.67 μM), and of compound 34 as a selective SP inhibitor (IC 50 = 3.26 μM). Image 1 COVID-19 pandemic, starting from the latest 2019, and caused by SARS-CoV-2 pathogen, led to the hardest health-socio-economic disaster in the last century. Despite the tremendous scientific efforts, mainly focused on the development of vaccines, identification of potent and efficient anti-SARS-CoV-2 therapeutics still represents an unmet need. Remdesivir, an anti-Ebola drug selected from a repurposing campaign, is the only drug approved, so far, for the treatment of the infection. Nevertheless, WHO in later 2020 has recommended against its use in COVID-19. In the present paper, we describe a step-bystep in silico design of a small library of compounds as main protease (MPpro) inhibitors. All the molecules were screened by an enzymatic assay on MPpro and, then, cellular activity was evaluated using Vero cells viral infection model. The cellular screening disclosed compounds 29 and 34 as in-vitro SARS-CoV-2 replication inhibitors at non-toxic concentrations (0.32 < EC50 < 5.98 mu M). To rationalize these results, additional in-vitro assays were performed, focusing on papain like protease (PLpro) and spike protein (SP) as potential targets for the synthesized molecules. This pharmacological workflow allowed the identification of compound 29, as a dual acting SARS-CoV-2 proteases inhibitor featuring micromolar inhibitory potency versus MPpro (IC50 = 1.72 mu M) and submicromolar potency versus PLpro (IC50 = 0.67 mu M), and of compound 34 as a selective SP inhibitor (IC50 = 3.26 mu M). (C) 2021 Elsevier Masson SAS. All rights reserved. |
| ArticleNumber | 113863 |
| Author | Di Matteo, Francesca Novi, Sara Sala, Marina Ostacolo, Carmine Snoeck, Robert Gomez-Monterrey, Isabel M. Vestuto, Vincenzo Musella, Simona Di Sarno, Veronica Bifulco, Giuseppe Andrei, Graciela Smaldone, Gerardina Bertamino, Alessia Lauro, Gianluigi Tecce, Mario Felice Ciaglia, Tania Scala, Maria Carmina Campiglia, Pietro Moltedo, Ornella |
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| Keywords | Enzymatic assays In-silico design Cellular characterization SARS-CoV-2 proteases dual inhibitor Biophysical assays COVALENT INHIBITORS MAIN PROTEASE DERIVATIVES |
| Language | English |
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| PublicationYear | 2021 |
| Publisher | Elsevier Masson SAS Elsevier |
| Publisher_xml | – name: Elsevier Masson SAS – name: Elsevier |
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| SubjectTerms | Animals Antiviral Agents - pharmacology Biophysical assays Cellular characterization Chemistry, Medicinal Chlorocebus aethiops Computer Simulation Drug Design Enzymatic assays In-silico design Life Sciences & Biomedicine Pharmacology & Pharmacy Protease Inhibitors - pharmacology SARS-CoV-2 - drug effects SARS-CoV-2 - enzymology SARS-CoV-2 proteases dual inhibitor Science & Technology Vero Cells |
| Title | Identification of a dual acting SARS-CoV-2 proteases inhibitor through in silico design and step-by-step biological characterization |
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