A new study published in the journal bioRxiv in April 2020 reports the identification of a promising multidrug treatment against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for causing COVID-19 disease. The team predicts that this combination will prevent the virus from reproducing, hence both halting the transmission and progress of the disease.
What issue did the researchers face?
The COVID-19 pandemic is affecting 185 countries and territories the world over, causing deaths by the tens of thousands, and slowing or arresting economic growth worldwide. Each week is seeing an increase of half a million cases and over 50,000 deaths. There is no approved treatment.
The unprecedented spread of the disease has sent researchers racing for a cure, as well as forcing them to evaluate existing therapies. Several already approved drugs, including lopinavir (LPV), ritonavir, chloroquine, favipiravir, and remdesivir, an antiviral awaiting approval have been repurposed and their efficacy in fighting COVID-19 is being evaluated.
The current study researches additional potential treatments, with a combination of nelfinavir and cepharanthine yielding promising preliminary results. The team included researchers from the National Institute for Infectious Diseases, Tokyo, and collaborating universities.
The researchers screened a panel of 306 drugs that have already been approved for use in various illnesses by the US Food and Drug Administration (FDA). This includes many that are currently under trial. The drugs were screened in a cell culture assay for SARS-CoV-2 infection. The virus infected the cells, leaving holes in the continuous sheet of cultured cells. This is called the cytopathic effect.
They identified nelfinavir and cepharanthine as having the most antiviral potential. These drugs were able to preserve cell viability 20 times more effectively than DMSO solvent control.
Nelfinavir inhibits the protease enzyme within the HIV virus, and thus prevents the virus from replicating. On the other hand, cepharanthine is an anti-inflammatory alkaloid drug derived from the plants of the genus Stephania.
To assess the degree of antiviral activity, the cells were then treated with the drugs at a range of concentrations. The viral RNA secreted from the cells was measured 24 hours after infecting the cells with the virus.
They found that both drugs reduced the amount of viral RNA significantly, proportional to the dose of the drug used. They assessed the toxicity of the drug in cultured cells and found that they operated within a 70-fold 'window of effectiveness' without significant toxicity.
The in vitro part of the study included time of addition analysis that showed the effect of the drugs on the virus. It was determined that these two drugs, nelfinavir, and cepharanthine, work by different mechanisms.
Docking simulations predicted that nelfinavir would interact with the main protease of the coronavirus and inhibits its replication. This drug will probably inhibit the recruitment of substrates for the enzyme by its interaction with the active site pocket of the main protease.
Cepharanthine prevents the virus from attaching to and entering cells. The CEP molecule binds to the spike glycoprotein of the virus and prevents it from engaging with the viral receptor. This is the angiotensin-converting enzyme 2 (ACE2).
Both the drugs show antiviral activity at therapeutic concentrations that fall within the levels already used in patients. The different mechanisms employed by the two drugs are synergistic, which increases their combined impact on the virus.
For instance, treatment with either nelfinavir (2.24 μM) or CEP (3.20 μM) caused a dose-dependent reduction in viral RNA to about 6% of that found in untreated controls. When both were used, the viral RNA fell to 0.07%. At higher doses viral RNA was undetectable. This synergistic activity is seen at multiple concentrations.
The use of mathematical modeling to represent the experimentally observed in vitro activity against the SARS-CoV-2 virus, together with the pharmacokinetics of the two drugs (already known from extensive earlier research pre-approval), enables the team to predict the ability of nelfinavir to promote the clearance of the virus from the body.
Nelfinavir alone could reduce the total viral load by 91%, leading to viral elimination in 12 days. This reduces the time for elimination of viral transmission by 4 days compared to untreated patients. CEP therapy alone did not show a significant effect on viral load, in the model, which the researchers attribute to the low viral load. Higher doses can probably be given since it has a low toxicity potential.
Both together led to a faster reduction in total viral load, and the levels were predicted to become undetectable a full 5.5 days earlier compared to no treatment.
If the two drugs are used together, the model shows a probable increase in effective inhibition of viral replication, arresting or slowing disease progression and reducing the transmissibility.
Several global research efforts are on to generate a COVID-19 vaccine targeting the SARS-CoV-2 encoded spike glycoprotein, which is vital to the attachment and entry of the virus into cells. The researchers stated that they expected cepharanthine to work alongside the vaccine to produce a far greater effect, due to its similar action. The team's observation that nelfinavir and cepharanthine targeted different steps of the virus's life cycle should encourage the development of combination therapies for COVID-19.
The combination is predicted to reduce the viral load in patients, which is suspected to be closely linked to both disease progression and transmission. Viral drug resistance may also be limited by using multiple drugs. The researchers say, "These agents offer a promising new multidrug treatment to combat COVID-19" in comparison to many other currently explored candidates.
Ohashi, H., Watashi K., Saso W., et al. (2020). Multidrug treatment with nelfinavir and cepharanthine against COVID-19. bioRxiv. doi: https://www.biorxiv.org/content/10.1101/2020.04.14.039925v1
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2020-04-20 01:44:55Z
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