In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camos...

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Published inViruses Vol. 15; no. 5; p. 1171
Main Authors Hassan, Ahmed H E, El-Sayed, Selwan M, Yamamoto, Mizuki, Gohda, Jin, Matsumoto, Takehisa, Shirouzu, Mikako, Inoue, Jun-Ichiro, Kawaguchi, Yasushi, Mansour, Reem M A, Anvari, Abtin, Farahat, Abdelbasset A
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 15.05.2023
MDPI
Subjects
Amidines
Antiviral agents
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Benzamidines - pharmacology
Cells
Coronavirus infections
Coronaviruses
COVID-19
COVID-19 vaccines
Drug therapy
Enzymes
Epidemics
Genomes
Health aspects
Humans
Infections
Influenza
Influenza A
Membrane fusion
Middle East respiratory syndrome
Middle East Respiratory Syndrome Coronavirus
Mutation
Pandemics
Pentamidine
Pharmacology, Experimental
Plasmids
Product development
Proteinase inhibitors
Proteins
Respiratory diseases
RNA polymerase
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
Testing
Thrombin
viral entry
Viral infections
Virus Internalization
Viruses
Egypt
United States > US
China
Germany
viral entry
antiviral agents
coronaviruses
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Abstract Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds - triggered potential TMPRSS2 inhibition with low micromolar IC concentrations, but they were less effective in cellular assays. Meanwhile, compound did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC value of 10.87 µM, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses.
AbstractList Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds 10–12 triggered potential TMPRSS2 inhibition with low micromolar IC50 concentrations, but they were less effective in cellular assays. Meanwhile, compound 14 did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC50 value of 10.87 µM, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound 14 inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound 14 as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses.
Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds 10 – 12 triggered potential TMPRSS2 inhibition with low micromolar IC 50 concentrations, but they were less effective in cellular assays. Meanwhile, compound 14 did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC 50 value of 10.87 µM, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound 14 inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound 14 as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses.
Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds - triggered potential TMPRSS2 inhibition with low micromolar IC concentrations, but they were less effective in cellular assays. Meanwhile, compound did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC value of 10.87 µM, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses.
Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than targeting the continuously mutating viral proteins, targeting the conserved host-based entry mechanism could offer advantages. Nafamostat and camostat were discovered as covalent inhibitors of TMPRSS2 protease involved in viral entry. To circumvent their limitations, a reversible inhibitor might be required. Considering nafamostat structure and using pentamidine as a starting point, a small set of structurally diverse rigid analogues were designed and evaluated in silico to guide selection of compounds to be prepared for biological evaluation. Based on the results of in silico study, six compounds were prepared and evaluated in vitro. At the enzyme level, compounds 10–12 triggered potential TMPRSS2 inhibition with low micromolar IC[sub.50] concentrations, but they were less effective in cellular assays. Meanwhile, compound 14 did not trigger potential TMPRSS2 inhibition at the enzyme level, but it showed potential cellular activity regarding inhibition of membrane fusion with a low micromolar IC[sub.50] value of 10.87 µM, suggesting its action could be mediated by another molecular target. Furthermore, in vitro evaluation showed that compound 14 inhibited pseudovirus entry as well as thrombin and factor Xa. Together, this study presents compound 14 as a hit compound that might serve as a starting point for developing potential viral entry inhibitors with possible application against coronaviruses.
Audience Academic
Author Farahat, Abdelbasset A
Shirouzu, Mikako
Hassan, Ahmed H E
Kawaguchi, Yasushi
Anvari, Abtin
Mansour, Reem M A
Gohda, Jin
Yamamoto, Mizuki
Matsumoto, Takehisa
El-Sayed, Selwan M
Inoue, Jun-Ichiro
AuthorAffiliation 5 Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
2 Research Center for Asian Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; mizuyama@g.ecc.u-tokyo.ac.jp (M.Y.); jgohda@g.ecc.u-tokyo.ac.jp (J.G.); ykawagu@g.ecc.u-tokyo.ac.jp (Y.K.)
4 Infection and Advanced Research Center (UTOPIA), The University of Tokyo Pandemic Preparedness, Tokyo 108-8639, Japan; jun-i@g.ecc.u-tokyo.ac.jp
6 Master of Pharmaceutical Sciences Program, California Northstate University, 9700 W Taron Dr., Elk Grove, CA 95757, USA; abtin.anvari8815@cnsu.edu
3 Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, Kanagawa 230-0045, Japan; takehisa.matsumoto@riken.jp (T.M.); mikako.shirouzu@riken.jp (M.S.)
7 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/37243257$$D View this record in MEDLINE/PubMed
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Issue 5
Keywords viral entry
antiviral agents
coronaviruses
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SSID ssj0066907
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Snippet Coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV and influenza A virus, require the host proteases to mediate viral entry into cells. Rather than...
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StartPage 1171
SubjectTerms Amidines
Antiviral agents
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Benzamidines - pharmacology
Cells
Coronavirus infections
Coronaviruses
COVID-19
COVID-19 vaccines
Drug therapy
Enzymes
Epidemics
Genomes
Health aspects
Humans
Infections
Influenza
Influenza A
Membrane fusion
Middle East respiratory syndrome
Middle East Respiratory Syndrome Coronavirus
Mutation
Pandemics
Pentamidine
Pharmacology, Experimental
Plasmids
Product development
Proteinase inhibitors
Proteins
Respiratory diseases
RNA polymerase
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
Testing
Thrombin
viral entry
Viral infections
Virus Internalization
Viruses
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Title In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases
URI https://www.ncbi.nlm.nih.gov/pubmed/37243257
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Volume 15
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