Different Aspects of Emetine’s Capabilities as a Highly Potent SARS-CoV-2 Inhibitor against COVID-19

Abstract

In the global movement to find the appropriate agents to fight the coronavirus disease of 2019 (COVID-19), emetine is one of the strongest anti-SARS-CoV-2 compounds with sub-micromolar EC 50 values, identified in several studies and high-throughput screening efforts. The reported anti-SARS-CoV-2 mechanisms indicate the effect of this compound on both virus-based and host-based targets. In addition to having excellent antiviral effects, emetine can relieve COVID-19 patients by reducing inflammation through inhibitory activity against NF-κB by the mechanism of IκBα phosphorylation inhibition; it can also limit the lipopolysaccharide-induced expression of pro-inflammatory cytokines TNFα, IL-1β, and IL-6. Emetine also can well reduce pulmonary arterial hypertension as an important COVID-19 complication by modulating a variety of cellular processes such as the Rho-kinase/CyPA/Bsg signaling pathway. The therapeutic value of emetine for combating COVID-19 was highlighted when in vivo pharmacokinetic studies showed that the concentration of this compound in the lungs increases significantly higher than the EC 50 of the drug. Despite its valuable therapeutic effects, emetine has some cardiotoxic effects that limit its use in high doses. However, high therapeutic capabilities make emetine a valuable lead compound that can be used for the design and development of less toxic anti-COVID-19 agents in the future. This Review provides a collection of information on the capabilities of emetine and its potential for the treatment of COVID-19, along with structural analysis which could be used for further research in the future.

Dual effects of ipecac alkaloids with potent antiviral activity against foot-and-mouth disease virus as replicase inhibitors and direct virucides

“…The ability of CPL and EMT to target the viral 3Dpol is consistent with previous studies demonstrating their inhibitory effects on RNA polymerases and reverse transcriptases of other viruses, such as ZIKV and HIV [ 25 , 39 , 43 , 44 ]. These alkaloids have been shown to intercalate with nucleic acids, disrupt viral protein translation, and impair cellular processes essential for viral replication.…”

“…For instance, EMT reacts with ZIKV NS5 RNA polymerase with an IC 50 of 121 nM [ 25 ], and it reduces HIV reverse transcriptase activity by approximately 50% at a concentration of 10 μM [ 44 ]. Moreover, CPL and EMT can block RNA synthesis at the active site of RNA-dependent RNA polymerase (RdRp) in an in vitro studies [ 25 , 39 ], which could provide supportive evidence that these two alkaloids exhibited their inhibition in our minigenome assay and an in silico prediction. Additionally, EMT disrupts cellular machinery, affecting translation of viral proteins, as observed in the inhibition of SARS-CoV-2 RNA synthesis, and the disruption of viral RNA binding with eukaryotic translation initiation factor 4E (eIF4E) [ 17 ].…”

“…Furthermore, CPL exhibits a structural difference in the isoquinoline core, featuring a hydroxyl functional group instead of a methoxyl group. This modification is hypothesized to reduce cytotoxicity and adverse effects [ 39 ]. Our results indicate that CPL is more potent against FMDV than emetine, suggesting that even lower doses might be effective for antiviral purposes.…”

Dual effects of ipecac alkaloids with potent antiviral activity against foot-and-mouth disease virus as replicase inhibitors and direct virucides

“…The ability of CPL and EMT to target the viral 3Dpol is consistent with previous studies demonstrating their inhibitory effects on RNA polymerases and reverse transcriptases of other viruses, such as ZIKV and HIV [ 25 , 39 , 43 , 44 ]. These alkaloids have been shown to intercalate with nucleic acids, disrupt viral protein translation, and impair cellular processes essential for viral replication.…”

“…For instance, EMT reacts with ZIKV NS5 RNA polymerase with an IC 50 of 121 nM [ 25 ], and it reduces HIV reverse transcriptase activity by approximately 50% at a concentration of 10 μM [ 44 ]. Moreover, CPL and EMT can block RNA synthesis at the active site of RNA-dependent RNA polymerase (RdRp) in an in vitro studies [ 25 , 39 ], which could provide supportive evidence that these two alkaloids exhibited their inhibition in our minigenome assay and an in silico prediction. Additionally, EMT disrupts cellular machinery, affecting translation of viral proteins, as observed in the inhibition of SARS-CoV-2 RNA synthesis, and the disruption of viral RNA binding with eukaryotic translation initiation factor 4E (eIF4E) [ 17 ].…”

“…Furthermore, CPL exhibits a structural difference in the isoquinoline core, featuring a hydroxyl functional group instead of a methoxyl group. This modification is hypothesized to reduce cytotoxicity and adverse effects [ 39 ]. Our results indicate that CPL is more potent against FMDV than emetine, suggesting that even lower doses might be effective for antiviral purposes.…”

Data Driven Computational Design and Experimental Validation of Drugs for Accelerated Mitigation of Pandemic-like Scenarios

“…The observed antiviral effect for DB07456_23_CH 3 _7_NO 2 showed better EC50 value (2.94 μM) than some of the other proposed antivirals for SARS-CoV-2, such as Remdesivir (EC 50 = 23.15 μM), Lopinavir (EC 50 = 26.63 μM), Ribavirin (EC 50 > 500 μM), Galidesivir (EC 50 > 100 μM), Ritonavir (EC 50 > 100 μM), Oseltamivir carboxylate (EC 50 > 100 μM), Baloxivir acid (EC 50 > 100 μM), and Favipiravir (EC 50 > 100 μM) . However, it had a higher EC50 value than Homoharringtonine (EC 50 = 2.55 μM) and Emetine (EC 50 = 0.46 μM). , Nonetheless, the improvement in the EC50 value of the DB07456_23_CH3_7_NO2 as compared to the parent, DB07456 (EC50 = 15.38 μM), indicates the merit of our framework in improving the performance of weaker ligands through functionalization, which may be imperative in time-sensitive situations.…”

CD40LG as a Biomarker in Rheumatoid Arthritis: Links to Bone Destruction and Interstitial Lung Disease ‐ A Bioinformatic Analysis With Clinical Validation

“…Emetine exhibits excellent antiviral activity and is capable of inhibiting the expression of pro‐inflammatory factors such as TNF‐α, IL‐1β, and IL‐6. Despite its potential cardiotoxicity, it remains one of the few highly effective anti‐SARS‐CoV‐2 drugs for the treatment of COVID‐19 [ 36 ]. Oligomycin A, an effective macrolide antibiotic, has been applied in the field of oncology, enhancing glycolysis in rectal cancer cells, promoting cell survival and proliferation, and reducing radiotherapy sensitivity, but it has higher toxicity and lower bioavailability [ 37 , 38 ].…”

Dual effects of ipecac alkaloids with potent antiviral activity against foot-and-mouth disease virus as replicase inhibitors and direct virucides

“…The ability of CPL and EMT to target the viral 3Dpol is consistent with previous studies demonstrating their inhibitory effects on RNA polymerases and reverse transcriptases of other viruses, such as ZIKV and HIV [ 25 , 39 , 43 , 44 ]. These alkaloids have been shown to intercalate with nucleic acids, disrupt viral protein translation, and impair cellular processes essential for viral replication.…”

“…For instance, EMT reacts with ZIKV NS5 RNA polymerase with an IC 50 of 121 nM [ 25 ], and it reduces HIV reverse transcriptase activity by approximately 50% at a concentration of 10 μM [ 44 ]. Moreover, CPL and EMT can block RNA synthesis at the active site of RNA-dependent RNA polymerase (RdRp) in an in vitro studies [ 25 , 39 ], which could provide supportive evidence that these two alkaloids exhibited their inhibition in our minigenome assay and an in silico prediction. Additionally, EMT disrupts cellular machinery, affecting translation of viral proteins, as observed in the inhibition of SARS-CoV-2 RNA synthesis, and the disruption of viral RNA binding with eukaryotic translation initiation factor 4E (eIF4E) [ 17 ].…”

“…Furthermore, CPL exhibits a structural difference in the isoquinoline core, featuring a hydroxyl functional group instead of a methoxyl group. This modification is hypothesized to reduce cytotoxicity and adverse effects [ 39 ]. Our results indicate that CPL is more potent against FMDV than emetine, suggesting that even lower doses might be effective for antiviral purposes.…”

Data Driven Computational Design and Experimental Validation of Drugs for Accelerated Mitigation of Pandemic-like Scenarios

“…The observed antiviral effect for DB07456_23_CH 3 _7_NO 2 showed better EC50 value (2.94 μM) than some of the other proposed antivirals for SARS-CoV-2, such as Remdesivir (EC 50 = 23.15 μM), Lopinavir (EC 50 = 26.63 μM), Ribavirin (EC 50 > 500 μM), Galidesivir (EC 50 > 100 μM), Ritonavir (EC 50 > 100 μM), Oseltamivir carboxylate (EC 50 > 100 μM), Baloxivir acid (EC 50 > 100 μM), and Favipiravir (EC 50 > 100 μM) . However, it had a higher EC50 value than Homoharringtonine (EC 50 = 2.55 μM) and Emetine (EC 50 = 0.46 μM). , Nonetheless, the improvement in the EC50 value of the DB07456_23_CH3_7_NO2 as compared to the parent, DB07456 (EC50 = 15.38 μM), indicates the merit of our framework in improving the performance of weaker ligands through functionalization, which may be imperative in time-sensitive situations.…”

CD40LG as a Biomarker in Rheumatoid Arthritis: Links to Bone Destruction and Interstitial Lung Disease ‐ A Bioinformatic Analysis With Clinical Validation

“…Emetine exhibits excellent antiviral activity and is capable of inhibiting the expression of pro‐inflammatory factors such as TNF‐α, IL‐1β, and IL‐6. Despite its potential cardiotoxicity, it remains one of the few highly effective anti‐SARS‐CoV‐2 drugs for the treatment of COVID‐19 [ 36 ]. Oligomycin A, an effective macrolide antibiotic, has been applied in the field of oncology, enhancing glycolysis in rectal cancer cells, promoting cell survival and proliferation, and reducing radiotherapy sensitivity, but it has higher toxicity and lower bioavailability [ 37 , 38 ].…”

Dual effects of ipecac alkaloids with potent antiviral activity against foot-and-mouth disease virus as replicase inhibitors and direct virucides

“…The ability of CPL and EMT to target the viral 3Dpol is consistent with previous studies demonstrating their inhibitory effects on RNA polymerases and reverse transcriptases of other viruses, such as ZIKV and HIV [ 25 , 39 , 43 , 44 ]. These alkaloids have been shown to intercalate with nucleic acids, disrupt viral protein translation, and impair cellular processes essential for viral replication.…”

“…For instance, EMT reacts with ZIKV NS5 RNA polymerase with an IC 50 of 121 nM [ 25 ], and it reduces HIV reverse transcriptase activity by approximately 50% at a concentration of 10 μM [ 44 ]. Moreover, CPL and EMT can block RNA synthesis at the active site of RNA-dependent RNA polymerase (RdRp) in an in vitro studies [ 25 , 39 ], which could provide supportive evidence that these two alkaloids exhibited their inhibition in our minigenome assay and an in silico prediction. Additionally, EMT disrupts cellular machinery, affecting translation of viral proteins, as observed in the inhibition of SARS-CoV-2 RNA synthesis, and the disruption of viral RNA binding with eukaryotic translation initiation factor 4E (eIF4E) [ 17 ].…”

“…Furthermore, CPL exhibits a structural difference in the isoquinoline core, featuring a hydroxyl functional group instead of a methoxyl group. This modification is hypothesized to reduce cytotoxicity and adverse effects [ 39 ]. Our results indicate that CPL is more potent against FMDV than emetine, suggesting that even lower doses might be effective for antiviral purposes.…”

Data Driven Computational Design and Experimental Validation of Drugs for Accelerated Mitigation of Pandemic-like Scenarios

“…The observed antiviral effect for DB07456_23_CH 3 _7_NO 2 showed better EC50 value (2.94 μM) than some of the other proposed antivirals for SARS-CoV-2, such as Remdesivir (EC 50 = 23.15 μM), Lopinavir (EC 50 = 26.63 μM), Ribavirin (EC 50 > 500 μM), Galidesivir (EC 50 > 100 μM), Ritonavir (EC 50 > 100 μM), Oseltamivir carboxylate (EC 50 > 100 μM), Baloxivir acid (EC 50 > 100 μM), and Favipiravir (EC 50 > 100 μM) . However, it had a higher EC50 value than Homoharringtonine (EC 50 = 2.55 μM) and Emetine (EC 50 = 0.46 μM). , Nonetheless, the improvement in the EC50 value of the DB07456_23_CH3_7_NO2 as compared to the parent, DB07456 (EC50 = 15.38 μM), indicates the merit of our framework in improving the performance of weaker ligands through functionalization, which may be imperative in time-sensitive situations.…”

CD40LG as a Biomarker in Rheumatoid Arthritis: Links to Bone Destruction and Interstitial Lung Disease ‐ A Bioinformatic Analysis With Clinical Validation

“…Emetine exhibits excellent antiviral activity and is capable of inhibiting the expression of pro‐inflammatory factors such as TNF‐α, IL‐1β, and IL‐6. Despite its potential cardiotoxicity, it remains one of the few highly effective anti‐SARS‐CoV‐2 drugs for the treatment of COVID‐19 [ 36 ]. Oligomycin A, an effective macrolide antibiotic, has been applied in the field of oncology, enhancing glycolysis in rectal cancer cells, promoting cell survival and proliferation, and reducing radiotherapy sensitivity, but it has higher toxicity and lower bioavailability [ 37 , 38 ].…”