We have now performed experiments in HT29 and HepG2 cells to test mitigation/synthetic lethality between remdesivir and drugs that impact mitochondrial function, following on our RNA-seq analysis showing reduced mitochondrial gene expression after remdesivir treatment (reproduced below:)
. Our cell line survival results are shown below:
In both cell lines, adenosine and syrosingopine rescue toxicity and ursodeoxycholic acid exacerbates toxicity. These effects are more pronounced in HT29.
Adenosine is easy to explain– it is a direct competitor of remdesivir (which is a modified adenosine derivative). So, under the hypothesis that remdesivir toxicity is caused by inhibition of mitochondrial RNA polymerase, the more wild-type adenosine available to the cell, the less RNA polymerase has to encounter remdesivir.
The results for Ursodeoxycholic acid and syrosingopine are more interesting, and these drugs can be posited as antagonistic at the level of mitochondrial function. Ursodeoxycholic acid has been shown to improve mitochondrial function, while syrosingopine has been shown to inhibit mitochondrial function through blocking lactate export and thus causing feedback inhibition of lactate dehydrogenase and inhibition of mitochondrial electron transport (see diagram from Benjamin et al 2018 https://doi.org/10.1016/j.celrep.2018.11.043 which depicts how this inhibition can kill cancer cells):
So, the hypothesis now becomes that mitochondrial activity in the presence of remdesivir is toxic, and by suppressing that activity, remdesivir toxicity can be mitigated.
We are currently exploring this idea further through CRISPR screening and RNA-seq. Because these results are in cell lines, we urge caution in interpreting them too strongly in context of mitigating possible remdesivir toxicity in patients, which may be a worthwhile goal to allow earlier and higher dose treatment. Adenosine treatment is likely to decrease remdesivir antiviral function since it is a direct competitor of remdesivir. It is unclear whether syrosingopine would impact remdesivir function.