Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
Hurting the virus by targeting the host
Abstract
Plitidepsin is a potent inhibitor of SARS-CoV-2 in vitro
Plitidepsin antiviral activity against SARS-CoV-2 is mediated through the inhibition of eEF1A
Plitidepsin shows in vivo antiviral efficacy in mouse models of SARS-CoV-2 infection
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26 February 2021
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- Kris M. White et al.
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RE: Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
A word of caution from decades of hard-won drug discovery R&D experience: be very careful of protein synthesis inhibitors. At sub-toxic concentrations they can do all sorts of therapeutic-looking things in cell-based assays that turn out under closer scrutiny to be what we used to call "sick cells doing weird things". To pick an egregious example, cycloheximide can yield intriguing results over a carefully selected concentration range in cell-based assays in a variety of therapeutic areas. The dose response curves for AV and cytotox assays in this report, with the relatively narrow window between EC50 and CC50 (where it can be unequivocally determined) are reminiscent of those observations.
RE: Aerosolized formulations of plitidepsin as chemovaccines against SARS-CoV-2 infection
In a pioneer study, White et al. (Jan 25th) reported the antiviral efficacy of plitidepsin against SARS-CoV-2 both in vitro and in animal models (1). The drug interacts with EF1A, a host protein that is needed for the translation of the subgenomic mRNA that codes for the coronaviral protein N. In this way, viral maturation is blocked and release of particles stops.
Based on the experience acquired from other RNA viruses, such as HIV and hepatitis C virus, we would like to highlight two major clinical implications derived from this work, which unfortunately were not discussed in the paper.
Firstly, the identification of a molecule that targets a host protein instead of a viral protein, might be viewed as an advantage. It may allow to overcome the expected challenge of selection of drug resistance, which always is a threat facing RNA viruses. It compromises the efficacy of many antivirals at least when given as monotherapy. In the HIV field, maraviroc is also an inhibitor of a host protein, the co-receptor CCR5, and resistance has only been reported occasionally. Moreover, the drug is relatively safe despite blocking a physiological inflammatory pathway.
Secondly, antivirals are mostly planned for treating individuals with establish infection. However, from the HIV field we have learned that the administration of antivirals before exposure may halt virus acquisition. This is known as pre-exposure prophylaxis and is widely used by persons engaged in high-risk sexual behaviors. With respect to SARS-CoV-2, it would be worth to explore whether aerosolized formulations of plitidepsin might reduce the chances of contagion.
The recent report of SARS-CoV-2 vaccine escape mutants highlights that vaccines most likely will not be the end of the pandemic. Updated or second generation vaccines will be required and complementary approaches, including the advent of antivirals used as chemovaccines (2), ultimately will benefit all in the fight against COVID-19.
RE: Preclinical Efficacy and Targeting of SARS-CoV-2 and COVID-19
The impressive research team reports on the preclinical efficacy through targeting the host protein.
It is found that the drug plitidepsin (aplidin), with limited clinical approval, possesses antiviral activity that is more potent than remdesivir against SARS-CoV-2 and COVID-19, with limited toxicity in cell culture and potent antiviral effects.
Whether the antiviral remdesivir, together with oxygen therapy and ventilation and the anti-inflammatory dexamethasone, should be used as a benchmark might be of some concern, especially with the advent of a number of approved vaccines.
It is also reported that a host-targeted antiviral might offer greater protection from viral escaped mutants, such as the UK variant or strain, than viral-targeted therapeutics and vaccines.
There was no mention of the mutated viruses from South Africa and Brazil, and possibly also from the USA, specifically California at this stage.
Although the experiments were performed on mice, the results look promising for future clinical trials on humans, especially if COVID-19 continues unabated for an extended period, as well as for future outbreaks of possibly more infectious coronaviruses.