Promising anti-SARS-CoV-2 drugs by effective dual targeting against the viral and host proteases
| Autor: | Sameh S. M. Soliman, Bahgat Fayed, Rania Hamdy, Ahmed M. Almehdi, Samia A. Elseginy, Noura Mahrous, Ahmed Mostafa |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Proteases
viruses medicine.medical_treatment Clinical Biochemistry Dual antiviral activity Pharmaceutical Science 01 natural sciences Biochemistry Antiviral Agents Virus Article chemistry.chemical_compound Drug Discovery medicine Humans Molecular Targeted Therapy Molecular Biology Furin IC50 Anti-Furin ComputingMethodologies_COMPUTERGRAPHICS chemistry.chemical_classification Protease biology Molecular Structure 010405 organic chemistry Chemistry SARS-CoV-2 Organic Chemistry COVID-19 0104 chemical sciences COVID-19 Drug Treatment 010404 medicinal & biomolecular chemistry Papain Anti-Mpro Enzyme biology.protein Vero cell Molecular Medicine Anti-PLpro Peptide Hydrolases |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters |
| ISSN: | 1464-3405 |
| Popis: | Graphical abstract SARS-CoV-2 caused dramatic health, social and economic threats to the globe. With this threat, the expectation of future outbreak, and the shortage of anti-viral drugs, scientists were challenged to develop novel antivirals. The objective of this study is to develop novel anti-SARS-CoV-2 compounds with dual activity by targeting valuable less-mutated enzymes. Here, we have mapped the binding affinity of >500,000 compounds for potential activity against SARS-CoV-2 main protease (Mpro), papain protease (PLpro) and human furin protease. The enzyme inhibition activity of most promising hits was screened and tested in vitro on SARS-CoV-2 clinical isolate incubated with Vero cells. Computational modelling and toxicity of the compounds were validated. The results revealed that 16 compounds showed potential binding activity against Mpro, two of them showed binding affinity against PLpro and furin protease. Respectively, compounds 7 and 13 showed inhibition activity against Mpro at IC50 0.45 and 0.11µM, against PLpro at IC50 0.085 and 0.063µM, and against furin protease at IC50 0.29µM. Computational modelling validated the binding affinity against all proteases. Compounds 7 and 13 showed significant inhibition activity against the virus at IC50 0.77 and 0.11µM, respectively. Both compounds showed no toxicity on mammalian cells. The data obtained indicated that compounds 7 and 13 exhibited potent dual inhibition activity against SARS-CoV-2. The dual activity of both compounds can be of great promise not only during the current pandemic but also for future outbreaks since the compounds’ targets are of limited mutation and critical importance to the viral infection. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect