SARS-CoV-2 E protein is a potential ion channel that can be inhibited by Gliclazide and Memantine

Tomar, Prabhat Pratap Singh; Arkin, Isaiah T.

doi:10.1016/j.bbrc.2020.05.206

Cited by 98 publications

(93 citation statements)

References 38 publications

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“…The permeability coefficient of Na + through artificial phospholipid membranes is \10 À14 cm s À1 , 119 so that any significant leakage must be due to ion channels in the viral envelop, almost certainly self-assembled homo-oligomers of 'protein E' in the influenza virus membrane, which is also present in SARS-CoV-2. 124,125 Interestingly, protein E ion channels have a marked preference for cations over anions, 124 so that leakage of NaCl may be limited by Cl À transport.…”

Section: Forcesmentioning

confidence: 99%

Soft matter science and the COVID-19 pandemic

et al. 2020

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Section: Forcesmentioning

confidence: 99%

Soft matter science and the COVID-19 pandemic

et al. 2020

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“…Previous studies with viroporins from different virus families have reported amantadine as a broadly functional inhibitor of ion channel activity[ 2 , 6 , 15 , 16 ]. Also, a recent study has reported Gliclazide and Memantine as potential inhibitors of E protein channel activity [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

In silico identification of Tretinoin as a SARS-CoV-2 envelope (E) protein ion channel inhibitor

Dey

Borkotoky

Banerjee

2020

Computers in Biology and Medicine

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Viroporins are oligomeric, pore forming, viral proteins that play critical roles in the life cycle of pathogenic viruses. Viroporins like HIV-1 Vpu, Alphavirus 6K, Influenza M2, HCV p7, and Picornavirus 2B, form discrete aqueous passageways which mediate ion and small molecule transport in infected cells. The alterations in host membrane structures induced by viroporins is essential for key steps in the virus life cycle like entry, replication and egress. Any disruption in viroporin functionality severely compromises viral pathogenesis. The envelope (E) protein encoded by coronaviruses is a viroporin with ion channel activity and has been shown to be crucial for the assembly and pathophysiology of coronaviruses. We used a combination of virtual database screening, molecular docking, all-atom molecular dynamics simulation and MM-PBSA analysis to test four FDA approved drugs - Tretinoin, Mefenamic Acid, Ondansetron and Artemether - as potential inhibitors of ion channels formed by SARS-CoV-2 E protein. Interaction and binding energy analysis showed that electrostatic interactions and polar solvation energy were the major driving forces for binding of the drugs, with Tretinoin being the most promising inhibitor. Tretinoin bound within the the lumen of the channel formed by E protein, which is lined by hydrophobic residues like Phe, Val and Ala, indicating its potential for blocking the channel and inhibiting the viroporin functionality of E. In control simulations, tretinoin demonstrated a lower binding energy with a known target as compared to SARS-CoV-2 E protein. This work thus highlights the possibility of exploring Tretinoin as a potential SARS-CoV-2 E protein ion channel blocker and virus assembly inhibitor, which could be an important therapeutic strategy in the treatment for coronaviruses.

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“…(67,122,123,125) This can be exemplified by the FDA-approved drugs gliclazide (17), a sulfonylurea administered to non-insulin-dependent diabetes mellitus patients, and memantine (18), an N-methyl-D-aspartate receptor antagonist used in the management of Alzheimer's disease, which have shown IC inhibitory activity in bacteria expressing SARS-CoV-2 E proteins. (126) Host cell targets -A key step in SARS-CoVs infection is the attachment of S protein to host angiotensinconverting enzyme 2 (ACE2), a membrane-bound carboxypeptidase (family: M2, clan: MA). (25,65,69) This enzyme catalyses the hydrolysis of angiotensin I and angiotensin II into angiotensin-(1-9) and angiotensin-(1-7) peptides, respectively.…”

Section: Sars-cov-2: Structure Mechanism Of Infection and Drug Targetsmentioning

confidence: 99%

“… 67 , 122 , 123 , 125 This can be exemplified by the FDA-approved drugs gliclazide (17), a sulfonylurea administered to non-insulin-dependent diabetes mellitus patients, and memantine (18), an N-methyl-D-aspartate receptor antagonist used in the management of Alzheimer’s disease, which have shown IC inhibitory activity in bacteria expressing SARS-CoV-2 E proteins. 126 …”

mentioning

confidence: 99%

COVID-19: molecular targets, drug repurposing and new avenues for drug discovery

Senger

Evangelista

Dantas

et al. 2020

Mem. Inst. Oswaldo Cruz

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Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious infection that may break the healthcare system of several countries. Here, we aimed at presenting a critical view of ongoing drug repurposing efforts for COVID-19 as well as discussing opportunities for development of new treatments based on current knowledge of the mechanism of infection and potential targets within. Finally, we also discuss patent protection issues, cost effectiveness and scalability of synthetic routes for some of the most studied repurposing candidates since these are key aspects to meet global demand for COVID-19 treatment.

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SARS-CoV-2 E protein is a potential ion channel that can be inhibited by Gliclazide and Memantine

Cited by 98 publications

References 38 publications

Soft matter science and the COVID-19 pandemic

Soft matter science and the COVID-19 pandemic

In silico identification of Tretinoin as a SARS-CoV-2 envelope (E) protein ion channel inhibitor

COVID-19: molecular targets, drug repurposing and new avenues for drug discovery

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