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Perspectives for repurposing drugs for the coronavirus disease 2019.

ABSTRACT: The newly emerged 2019 novel coronavirus (CoV), named as severe acute respiratory syndrome CoV-2 (SARS-CoV-2), like SARS-CoV (now, SARS-CoV-1) and Middle East respiratory syndrome CoV (MERS-CoV), has been associated with high infection rates with over 36,405 deaths. In the absence of approved marketed drugs against coronaviruses, the treatment and management of this novel CoV disease (COVID-19) worldwide is a challenge. Drug repurposing that has emerged as an effective drug discovery approach from earlier approved drugs could reduce the time and cost compared to de novo drug discovery. Direct virus-targeted antiviral agents target specific nucleic acid or proteins of the virus while host-based antivirals target either the host innate immune responses or the cellular machineries that are crucial for viral infection. Both the approaches necessarily interfere with viral pathogenesis. Here we summarize the present status of both virus-based and host-based drug repurposing perspectives for coronaviruses in general and the SARS-CoV-2 in particular.

SUBMITTER: Cherian SS

PROVIDER: S-EPMC7357399 | biostudies-literature | 2020 Feb & Mar

REPOSITORIES: biostudies-literature

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Perspectives for repurposing drugs for the coronavirus disease 2019.

Cherian Sarah S SS Agrawal Megha M Basu Atanu A Abraham Priya P Gangakhedkar Raman R RR Bhargava Balram B

The Indian journal of medical research 20200201 2 & 3

The newly emerged 2019 novel coronavirus (CoV), named as severe acute respiratory syndrome CoV-2 (SARS-CoV-2), like SARS-CoV (now, SARS-CoV-1) and Middle East respiratory syndrome CoV (MERS-CoV), has been associated with high infection rates with over 36,405 deaths. In the absence of approved marketed drugs against coronaviruses, the treatment and management of this novel CoV disease (COVID-19) worldwide is a challenge. Drug repurposing that has emerged as an effective drug discovery approach fr ...[more]

PMID: 32317408

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Project description:BACKGROUND:Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model. METHODS:A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively. RESULTS:The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 ?mol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 ?mol/L. The viral RNA yield in cells treated with 10 ?mol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48?±?0.02]?×?10vs. 1.00?±?0.12, t?=?150.38, P?<?0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 ?mol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46?±?0.12, vs.1.00?±?0.37, t?=?2.42, P?<?0.05) and viral replication ([6.18?±?0.95]?×?10vs. 1.00?±?0.43, t?=?3.98, P?<?0.05). CONCLUSIONS:Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.

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Perspectives for repurposing drugs for the coronavirus disease 2019.

Publications

Perspectives for repurposing drugs for the coronavirus disease 2019.

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