Here’s something that might be alarming for the companies that have been piling into the hepatitis C space (Gilead, BMS, Merck and more). But if you’re a hepatitis C patient, or the insurance company of one, it might be welcome. A new report suggests that an existing antihistamine, chlorcyclizine (CCZ), could be an effective therapy. Check out that structure – that’s a first-generation antihistamine if you ever saw one (the old fuzzy-headed allergy season effect). It’s been over-the-counter for dog’s years; in the US it mostly seems to be sold as part of the usual combinations for allergy et al.
But this new paper, from NIH and a collaborator at Hiroshima University, makes a good case for it as an antiviral. A cell-based phenotypic assay identified it in a screen of approved drugs, and several related compounds hit as well. Both enantiomers of CCZ seemed to work, so they chose the (S), since it had less histamine receptor activity. It dose-responsed well in assays measuring viral RNA levels in infected cells, and the activity seems to cross all the viral genotypes tested, without any noticeably cytotoxicity. Follow-up assays showed that viral RNA replication doesn’t seem to be the target, nor virion assembly. It’s back earlier than those, and the best hypothesis now is that it’s a cell entry inhibitor. But none of the proteins known to be factors in HCV cell entry appear to be affected, so the target hunt is still very much on.
That unique mode of action would make you think that it would synergize well with the existing HCV drugs, and so it proved – it enhanced the activity of everything on the list. But it’s not a pan-viral panacea: tests against a whole list of other disease-causing viruses showed no useful activity, even against another flavivirus like dengue. So far, there’s also been an interesting lack of resistant strains developing. Someone’s going to uncover some good biology using this compound, that much seems certain.
Pharmacokinetics in mice are reasonable, and (helpfully) the compound attains higher concentrations in the liver than in circulation. It does indeed cross the blood-brain barrier, as all the old antihistamines do, so that would have to be taken into account at the doses needed for an antiviral program. But the desmethyl metabolite, nor-CCZ, seems also quite potent as an antiviral, and doesn’t cross nearly as much (as you’d expect; the same thing shows up for other known antihistamines). So that one would have fewer side effects, presumably, but would need to be developed as a completely new drug, whereas chlorcyclizine has been around since the Johnson administration.
In summary, this study provides compelling evidence that CCZ, an over-the-counter allergy drug, has a strong anti-HCV activity in vitro and in vivo in a mouse model of HCV infection. On the basis of these results, a clinical assessment of CCZ alone and in combination with other anti-HCV drugs is warranted. The repurposing or repositioning of CCZ in HCV treatment may provide a more affordable alternative to the current costly options, especially in low-resource settings where chronic HCV infection is endemic. This study also lays the foundation for further structure modification of CCZ to discover more optimal analogs for the treatment of HCV infection.
It also points the way to finding a very interesting new antiviral target, too, as mentioned above. This is just the sort of thing that you run phenotypic screens in order to find – congratulations to the NIH/Hiroshima team for really hitting a good one.