Monday, April 30, 2018

Chasing the "One Drug" to Rule Them All

Chasing the "One Drug" to Rule Them All
(All meaning all the hemorrhagic fever viruses)

By Jesica Levingston Mac leod, PhD

Almost all the hemorrhagic fever viruses are listed by the World Health Organization to be only handled in Biohazard level 4 facilities, as they are potential agents of bioterrorism. These are also RNA viruses, which have a mortality ratio between 30 to 90% and there are no vaccines or effective treatment methods available. In fact, the recommended anti viral treatment; Ribavirin has not shown to be very successful in a randomized-controlled trial, as Ribavirin was not superior to no Ribavirin treatment in mortality rates. One would think that these types of viruses could only arise in far and remote regions like Argentina (in the case of Junin virus) or Congo (like the Ebola virus). However with the increase in the intercontinental travels these viruses could be closer than what you would expect.

But not all is bad news: Lu et al. examined the effect of inhibitors based on a host protein (Tsg101), and discovered an inhibitor for at least 2 negative stranded RNA viruses (Junin virus and Ebola virus). Compound 0013 could reduce Junin virus egress dissemination and disease progression in infected individuals by inhibiting the viral nucleoprotein-Tsg101 interaction. Moreover, since this Tsg101 related recruitment system is utilized by other RNA virus pathogens (e.g. Ebola virus and HIV-1), the compound 0013 has the potential to function as a broad-spectrum, host-oriented antiviral drug.

In a more advance stage of drug development, in a recent Nature article, Warren et al. showed that a compound: BCX4430, inhibits infection of Ebola and Marburg virus in human cells. Furthermore, the post exposure of this compound in rodents also protects against further viral infections. BCX4430 is a novel synthetic adenosine analogue that inhibits viral RNA polymerase function. The hallmark is that BCX4430 protects macaques from Marburg virus infection when administered as late as 48 hours after infection. Finally, BCX4430 exhibits broad-spectrum antiviral activity against other viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses.

Lastly, in the Science magazine, Andrews et al. showed the efficiency of the compound GSK744 in protecting macaques against HIV infection. This drug is an integrase strand-transfer inhibitor that has been formulated as a long-acting injectable. GSK744 was administered at two time points 4 weeks apart, beginning 1 week before virus administration, and the macaques were challenged weekly for 8 weeks. GSK744, protected all animals against repeated low-dose challenges. These results suggest that GSK744 could potentially decrease adherence problems associated with daily preexposure prophylaxis and may be administered quarterly in humans. And, of course, this compound has been suggested to be use as an inhibitor for other RNA viruses.

As you can see, not all the researchers involved in drug discovery are only focus in their own virus of interest or are as avid to put the drugs in the market before passing with honors all the FDA approval test, as the movie “Dallas Buyers Club” showed us recently.

The drug discovery process is very extensive, exhausting and expensive; in order pass the reach the pre-clinical and clinical testing to pass the stringent FDA approval. Therefore, finding “the drug” than can be effective against a variety of viruses (and not toxic for humans!) could be a shortcut in medicine development.

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