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Wednesday, 4 May 2011

Drug Repurposing: HIV PR inhibitors against Leishmania spp.



I came across this interesting paper from earlier this year - "HIV proteinase inhibitors target the Ddi1-like protein of Leishmania parasites", published in FASEB J. HIV protease inhibitors were known to decrease levels of Leishmania in vivo, but the molecular target was not known. This paper shows that HIV-1 proteinase inhibitors are probably functional inhibitors of Ddi1 from Leishmania spp. Nelfinavir (the structure above) is a 440 nM IC50 inhibitor of L. major Ddi1 (and weaker against the human ortholog 3.3 uM). This is on the face of it, a lovely example of drug repositioning - the use of a drug for a new, and in this case, a non-obvious use.

HIV-1 PR (UniProt:Q9YQ34) and Ddi1 (UniProt:A4H334) are both aspartyl proteinases (Pfam:CL0129), share a common mechanism, and overall architecture (although HIV-PR is a homodimer, and Ddi1 is a single chain containing two 'copies' of the HIV-PR sequence). There is a human Ddi1 ortholog as well (UniProt:Q8WTU0), and poking around in UniProt shows there is a Tryp orthologue as well, but not an obvious Plasmo one - but I haven't really looked too hard, so far.

It is interesting to speculate what would be the most efficacious/potent launched/clinical stage HIV-1 PR inhibitor for the treatment of Leishmaniasis - and probably homology modelling and docking could allow a pretty good guess at this.

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