At this very early point in the emerging 2019-nCoV outbreak, knowledge about the virus is insufficient to predict what shape that outbreak will ultimately take. But knowledge about the virus is accumulating at remarkable speed, and experience with other viruses is helping to shape the response to the newest coronavirus threat.
2019-nCoV, sometimes called Wuhan coronavirus after its source, is the third coronavirus after SARS-CoV and MERS-CoV with the potential to cause serious illness and death that has emerged since the beginning of the 21st century. The earlier emergence of SARS and MERS prompted screening efforts to find drugs that could be deployed against coronaviruses. Now, those screens have enabled rapid testing of repurposed drugs in 2019-nCoV patients.
In 2016 and 2018, respectively, researchers at the University of North Carolina and Vanderbilt University reported that remdesivir (GS-5734, Gilead Sciences Inc.), which was then in clinical development for treatment of Ebola virus disease, inhibited SARS-CoV and MERS-CoV replication in vitro and in mice. Remdesivir is a nucleoside prodrug that works by inhibiting viral RNA transcription. “Uridine nucleoside analogues (which can incorporate selectively into RNA) or replication chain-terminators are good bets as targets, especially if toxicity studies show that they can be well-tolerated,” Rachel Graham told BioWorld.
Graham is an assistant professor of epidemiology at the University of North Carolina’s Gillings School of Global Public Health, and part of the research group that identified remdesivir’s activity against SARS and MERS coronaviruses.
Remdesivir was unsuccessful as an Ebola drug, proving less effective than several other drugs.
But the work of Graham, principal investigator Ralph Baric and Mark Denison, and their colleagues flagged the drug as a possible coronavirus treatment, prompting its compassionate use in the first identified 2019-nCov case in the U.S.
That case, a 35-year-old man who had traveled to Wuhan in early January to visit family, was identified on Jan. 20, when he visited an emergency room in Seattle after developing respiratory symptoms. On Jan. 26, he was treated with remdesivir after developing pneumonia. His symptoms improved almost immediately, prompting the initiation of a phase III trial in China.
Another possible repurposing candidate is the HIV drug Aluvia (lopinavir/ritonavir, Abbvie Inc.), which will also be investigated in a clinical trial in China for the treatment of 2019-nCoV. Abbvie said it has donated almost $1.5 million worth of pills in response to a request by Chinese health authorities.
Lopinavir is a protease inhibitor, while ritonavir increases the half-life of lopinavir by inhibiting cytochrome P450.
Graham said that “proteases are sometimes a good target; however, coronavirus proteases have broad specificities, and inhibiting them might unduly harm the host cell.” HIV proteases are more specific in their effects, which is why Aluvia can specifically inhibit viral proteases without such toxicity.
Aluvia in combination with interferon-beta is being tested clinically for the treatment of MERS-CoV in the Kingdom of Saudi Arabia, and a paper published in the Jan. 10, 2020, issue of Nature Communications directly compared the effects of remdesivir and Aluvia on MERS-CoV in mouse experiments.
In mice and for MERS, at least, remdesivir and interferon-beta beat out Aluvia.
The authors wrote that “both prophylactic and therapeutic [remdesivir] improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic [Aluvia plus interferon-beta] slightly reduces viral loads without impacting other disease parameters.”
Screening is rapidly yielding other potential additions to the arsenal.
In the Feb. 4, 2020, issue of Cell Research, scientists from the Wuhan Institute of Virology reported in a letter to the editor that the antimalarial drug chloroquine was roughly as effective as remdesivir at inhibiting 2019-nCoV in vitro.
And according to Chinese state media, scientists from the Shanghai Institute of Materia Medica (SIMM, under the Chinese Academy of Sciences) and the Wuhan Institute of Virology found that the traditional Chinese Medicine Shuanghuanglian could be used to inhibit 2019-nCoV. (See story in this issue.)
Not surprisingly, attempts to directly screen for compounds that are effective against 2019-nCov are also quickly getting underway. Graham and her colleagues are among the researchers undertaking such screening, mainly in chemical libraries.
“When treating a replicating RNA virus, the best targets are those that can be affected early in the virus’ life cycle, or else viral targets that are specific to the virus,” she said.
Editor’s Note: This is the first of a two-part series exploring how experience with other viruses is being used to understand and rapidly respond to the emergence 2019-nCoV. Part 2 will run in the Feb. 5 issue.