SARS-CoV-2: Remdesivir and Chloroquine effectively inhibit the novel coronavirus in vitro

In December 2019, a novel pneumonia caused by a previously unknown pathogen emerged in Wuhan, a city of 11 million people in central China.
The initial cases were linked to exposures in a seafood market in Wuhan.
As of January 27, 2020, the Chinese authorities reported 2835 confirmed cases in mainland China, including 81 deaths. Additionally, 19 confirmed cases were identified in Hong Kong, Macao and Taiwan, and 39 imported cases were identified in Thailand, Japan, South Korea, United States, Vietnam, Singapore, Nepal, France, Australia and Canada.

The pathogen was soon identified as a novel coronavirus ( 2019-nCoV ), which is closely related to severe acute respiratory syndrome CoV ( SARS-CoV ).
The novel coronavirus, 2019-nCov, was named as SARS-CoV-2 by ICTV Coronaviridae Study Group on February 12, 2020.

Currently, there is no specific treatment against the new virus. Therefore, identifying effective antiviral agents to combat the disease is urgently needed.
An efficient approach to drug discovery is to test whether the existing antiviral drugs are effective in treating related viral infections.

The 2019-nCoV belongs to Betacoronavirus which also contains SARS-CoV and Middle East respiratory syndrome CoV ( MERS-CoV ).
Several drugs, such as Ribavirin, Interferon, Lopinavir - Ritonavir, corticosteroids, have been used in patients with SARS or MERS, although the efficacy of some drugs remains controversial.3

Remdesivir has been recently recognized as a promising antiviral drug against a wide array of RNA viruses ( including SARS / MERS-CoV5 ) infection in cultured cells, mice and nonhuman primate ( NHP ) models. It is currently under clinical development for the treatment of Ebola virus infection.
Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination.
The time-of-addition assay showed Remdesivir functioned at a stage post virus entry, which is in agreement with its putative anti-viral mechanism as a nucleotide analogue.
In NHP model, intravenous administration of 10 mg/kg dose of Remdesivir resulted in concomitant persistent levels of its active form in the blood ( 10 μM ) and conferred 100% protection against Ebola virus infection.
The data showed that EC90 value of Remdesivir against 2019-nCoV in Vero E6 cells was 1.76 μM, suggesting its working concentration is likely to be achieved in NHP.
Preliminary data showed that Remdesivir also inhibited virus infection efficiently in a human cell line ( human liver cancer Huh-7 cells ), which is sensitive to 2019-nCoV.2

Chloroquine, a widely-used anti-malarial and autoimmune disease drug, has recently been reported as a potential broad-spectrum antiviral drug.
Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV.
The time-of-addition assay demonstrated that Chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells.
Besides its antiviral activity, Chloroquine has an immune-modulating activity, which may synergistically enhance its antiviral effect in vivo.
Chloroquine is widely distributed in the whole body, including lung, after oral administration.
The EC90 value of Chloroquine against the 2019-nCoV in Vero E6 cells was 6.90 μM, which can be clinically achievable as demonstrated in the plasma of rheumatoid arthritis patients who received 500 mg administration.
Chloroquine is a cheap and a safe drug that has been used for more than 70 years and, therefore, it is potentially clinically applicable against the 2019-nCoV.

The findings have revealed that Remdesivir and Chloroquine are highly effective in the control of 2019-nCoV infection in vitro.
Since these compounds have been used in human patients with a safety track record and shown to be effective against various ailments, they should be assessed in human patients suffering from the novel coronavirus disease. ( Xagena )

Source: Wang R et al, Cell Research, 2020



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