A new route of treatment against Covid-19

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The combination of remdesivir with diltiazem gives very promising preclinical results against the Covid-19 virus. A human test is expected to see the light of day in the coming months.

Treatment research continues to mobilize scientists. In this dynamic, promising preclinical results have just been published in the journal Cell Reports Medecine on the association of remdesivir with a repositioned drug: diltiazem.

An innovative method of research in antiviral treatments.

In the laboratory, for several years, a repositioning strategy has been followed for medications that are already on the market for new therapeutic indications, particularly anti-infectives. A technical term for a simple reality: a drug is authorized to be marketed for a given medical indication, the idea is to test it and, if necessary, reposition it, for the treatment of other pathologies.

You probably know the story of the famous blue pill. Viagra was not originally intended for current use at all. Pfizer actually claimed the molecule (sildenafil citrate, known for its ability to dilate blood vessels) for the treatment of angina. In clinical trials, the molecule has been shown to be insufficiently effective in treating this condition, and unexpected and, to say the least, surprising side effects have been observed. Therefore, it is based on a fortuitous observation during its clinical development that the molecule has been repositioned for a new therapeutic indication.

To avoid relying on chance discovery of unpredictable effects, a rational scientific strategy for in situ drug detection has been developed and validated in the laboratory. This strategy is based on the characterization by high performance sequencing and on the analysis through artificial intelligence tools of chemogenomic and virogenomic signatures, which in some way constitute the cell fingerprints left by drugs and pathogens, respectively.

Remdesivir is an example of a repositioned drug: a molecule initially in development to fight the Ebola virus, and for which antiviral activity against SARS-CoV-2 (Covid-19 virus) has been shown in various preclinical models and potential for accelerate the healing time in hospitalized patients. The clinical results, still incomplete, support the use of remdesivir to treat Covid-19, but, by itself, it is not effective in reducing the mortality rate in patients with severe forms of the pathology.

This strategy can not only reduce the risk of developing viral resistance, but also achieve broad-spectrum antiviral effects. One of the goals is also to be able to combine these repositioned drugs that target respiratory epithelial cells (virus factories) with conventional antivirals to enhance the effect. A first proof of concept was performed on influenza viruses with the identification and repositioning of diltiazem, a drug on the market for its antihypertensive properties, as an influenza virus inhibitor in several preclinical models.

To test the therapeutic efficacy of candidate molecules against SARS-CoV-2, in vitro infection models have also been implemented and characterized, particularly based on reconstituted human respiratory epithelia of nasal, bronchial and alveolar origin. Composed of different primary epithelial cells (ciliated, mucus-secreting, Clara cells, basal), organized in tissues, these models are very physiological and predictive, as described in the study recently published in the journal Nature on the ineffectiveness of hydroxychloroquine in a model of non-human primates.

A large number of candidate molecules have been evaluated in these models, including two molecules of interest: remdesivir and diltiazem, as monotherapy and in combination. The results of this study show a significant reduction in viral load in epithelia infected with SARS-CoV-2 when treated with remdesivir. This effect is enhanced when diltiazem is added in combination. By stimulating the innate immune response of epithelia, diltiazem enhances the effect of remdesivir and offers the opportunity to reduce human doses.

Towards a clinical trial

Preclinical trials with this dual therapy in animal models continue and it is expected that a clinical trial can be launched in the coming months if the positive results are confirmed. Other combinations of repositioned drugs are also being explored.

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