Referee 2's review:

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.
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Tribouillard-Travier et al have submitted the article "Antihypertensive drug Guanabenz is active in vivo against both yeast and mammalian prions" to PLoS One. The authors, using a yeast-based screening method developed by their lab, have presented data proposing that the a2-adrenergic agonist Guanabenz can act as an antiprion agent. They furthered their findings by using additional cell-based and animal-based studies in support of the antiprion effect of Guanabenz. Modest synthetic chemistry attempts were made that began to address the significant chemical groups of Guanabenz that contribute to its effects.

The paper is well written and methodical. The story would clearly be strengthened by understanding the mechanism involved in the action of Guanabenz, since it appears to be independent of the a2-adrenergic effect. A brief discussion of other known pathways impacted by Guanabenz, if known, would be useful. A second means of greatly strengthening the story would be a more aggressive rational approach to modifying, then testing, derivatives of Guanabenz in their ability to act as antiprion agents. Ultimately, as stated before, a mechanism is critical. However, this paper is a nice contribution to the field and will add a possible platform for further developments.

With that said, one item that must be corrected prior to acceptance is the misleading and incorrect 'concentration-response curve' in Figure 2b. The main problem is that it is plotted on a linear graph but a sigmoidal curve is represented, which is properly only observed in a logarithmic scale, if it is indeed a pharmacological effect that is being observed. Thus, making a statement of an 'IC50' with the data points in impossible as only 1 real data point exists above the proposed 'IC50', the concentrations used do not span even one log, and if the data is correct as shown, the interpretation would be that the effect is not pharmacological. Also, multiple experiments would need to be done along with statistics. Thus, my suggestion would be to not show the curve, not make a statement about IC50, and to just show the western blot and make the statement that Guanabenz shows antiprion effects at low micromolar concentrations.

One minor point that could help the paper appeal to a larger readership would be to hypothesize/discuss what may be different in the assay systems used that allowed Tacrine to appear to act as an antiprion agent in the yeast-based system but not in the cell-based system.

In conclusion, I would accept this paper for publication in PLoS One once the pseudo-pharmacology is correct.