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Nucleos(t)ide analogues have been successfully used to treat HIV, HBV and HCV. Since rabies virus is also a RNA virus that uses RdRp to replicate. If we develop an nucleos(t)ide against its RdRp, will it be able to save rabies victims? What would be potential obstacles?

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  • $\begingroup$ Are you referring to RNA interference? Can you link some sources about the one used for HIV, HBV etc. ? $\endgroup$ – alec_djinn Oct 11 '16 at 6:13
  • $\begingroup$ No. I mean this en.m.wikipedia.org/wiki/Nucleoside_analogue $\endgroup$ – Ballistics Oct 11 '16 at 6:18
  • $\begingroup$ Examples include Tenofovir to HIV, Entecavir to HBV and Sofosbuvir to HCV. Nucleos(t)ide analogues can serve as substrates of viral polymerase and incorporate into the newly synthesized nucleic acid chain. But it can prevent further incorporation, thereby terminate viral nucleic acid replication. $\endgroup$ – Ballistics Oct 11 '16 at 6:22
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In theory that would be possible, as you mentioned the rabies virus does have its particular polymerase, and adequate inhibiting substrates could possibly be found.

On the other hand, the current immunoglobulin and vaccination post-exposure scheme is quite effective, and the incidence of rabies in developped countries is pretty low; so it's unlikely an inhibitor could profitably be developped to the market. That means rabies-directed nucleoside analogues are not priority target for pharma companies, IMO the biggest obtacle.


Here are some of the technical hurdles a drug candidate would have to overcome, as a nucleoside analogue :

  • Affinity to the viral polymerase : too low an affinity makes competition with the native substrate difficult

  • Rate of conversion to triphosphate form : a low affinity of the host nucleoside kinase to the analogue can cause a inadequate concentration of active triphosphated inhibitor. Some virus (HSV) have their own kinase that may be less selective, though that doesn't seem to be the case for the rabies virus.

  • Selectivity for the viral polymerase (versus the host replication/transcription machinery) : a cause of cytotoxicity and, generally, adverse effects.

  • Pharmacokinetic problems : the analogue has to be able to be taken in through nucleoside transporters (facilitated transport into the cell), or go through other means of active transport, as that kind of compound is usually quite hydrophilic. One could also use the usual prodrug tricks to pass the membrane (see CP-4055 or sapacitabine). This may be particularly problematic for acute-stage rabies, as there would be the blood-brain barrier to pass.


Some additional perspectives on the development of nucleoside analogues

Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases -- (http://www.nature.com/nrd/journal/v12/n6/full/nrd4010.html)

Discovery and development of clofarabine: a nucleoside analogue for treating cancer -- (http://www.nature.com/nrd/journal/v5/n10/full/nrd2055.html)

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