I’ve been meaning to write about this paper for some time…

Viruses continue to cause extensive morbidity, mortality and not to mention economic stress, worldwide by infecting and causing disease in humans, animals and plants. Vaccines have been able to control many of the major viral diseases (smallpox, rinderpest, polio, measles…) but the development of vaccines against all viral pathogens is unrealistic and inefficient with current methods of R and D, testing and production.

When you consider the numbers of currently unknown, uncharacterised viruses replicating in reservoirs of animals or plants that have the potential to jump species (e.g MERS-CoV) and cause outbreaks (ebolavirus), epidemics (nipah) or even pandemics (influenza) then the thinking that generating vaccines against all these viruses becomes even more untenable. Even to generate specific antiviral drugs against them all becomes impossible.

This is why we have a back-up plan. This is why we broad-spectrum antivirals. Broad spectrum antivirals are drugs that will inhibit diverse viruses and are usually based upon targeting a common phenotype linking all the viruses (RNA dependant RNA polymerase, neuraminidase enzyme, RNA genome, RNA dependant DNA polymerase). These drugs tend to suffer from a number of problems 1) they aren’t all that broad spectrum, 2) resistance to antivirals can evolve rapidly and 3) we simply need more broad spectrum options.

This is why I have chosen the following paper for #microtwjc :

A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion.

The paper describes an international collaboration between virologists and chemists that resulted in the development of a novel, highly effective, broad spectrum antiviral molecule that has little affect on the functioning of the host cell. The interesting thing is that the molecule inhibits virus – to – cell fusion of the viral envelope with the host cell plasma membrane, i.e one of the most important early steps in the virus (obligate intracellular parasite) lifecycle.

(the drug was originally described here: http://www.ncbi.nlm.nih.gov/pubmed/20133606)

Some points on the paper:

1) They know at what point the molecule inhibits (a late stage in virus-to-cell fusion).
2) They know that it leads to the oxidation of fatty acids in all membranes. (but only affects viral ones)
3) They know to do so it has to generate oxygen free radicals in the presence of light
4) Fatty acid oxidation changes membrane properties to prevent fusion of one membrane to another. 
5) They can optimise the molecular to make it even more effective
6) It works to some degree in vivo, but cannot wholly prevent virus-induced disease and death.

And here are some discussion points:

A) do we really need broad-spectrum antivirals? Who is going to have access to these?
B) Is virus envelope fusion a good target? What about non enveloped viruses? What about viruses that can spread via cell-to-cell fusion with limited virus-to-cell?
C) Would these drugs induce viral resistance evolution?
D) Oxidisation of viral lipids sounds a good idea, how come evolution has not come up with this idea already? …Or has it?
E) In vivo it don’t look so good. How come? Can it be made better?