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Treating sleeping sickness

PSI-SGKB [doi:10.1038/fa_psisgkb.2010.16]
Featured Article - May 2010
Short description: A potential new drug kills the bloodstream parasite that causes this disease.

X-ray crystal structure of DDD85646 bound to LmN-myristoyltransferase.

African sleeping sickness, also known as human African trypanosomiasis, kills 30,000 people each year, and there is currently no effective and safe treatment. Frearson et al. from the University of Dundee, in collaboration with the University of York and the Structural Genomics Consortium in Toronto, report a new potential drug that kills the bloodstream parasite that causes this disease.

N-myristoylation is an important eukaryotic modification required for many biological processes. In the parasite that causes sleeping sickness, Trypanosoma brucei, this reaction is catalysed by N-myristoyltransferase, which has at least 60 substrates and is probably involved in many downstream processes. The central role of this enzyme suggested that its inhibition might be an effective way to treat the disease.

This isn't the first time N-myristoyltransferase has attracted attention though. It has been investigated as a potential anticancer, antiviral and antifungal target, too, and looks promising as a drug target because it is possible to distinguish between the human and the parasitic form. Unfortunately, no useful and safe inhibitors have been identified until now.

But anti-fungal N-myristoyltransferase programs were discontinued because of an inability to identify broad spectrum inhibitors. And as for cancer treatment, no one has yet identified potent human N-myristoyltransferase inhibitors with which to fully validate this enzyme.

Frearson et al. screened 62,000 compounds for a potential lead and eventually identified one, DDD85646, that inhibits N-myristoyltransferase and prevents growth of T. brucei. Testing of this potential drug in a mouse model of human African trypanosomiasis proved successful, with all mice cured of this disease when the compound was taken orally. Even mice with a clinically relevant form T. brucei rhodesiense were cured.

These promising results against T. brucei in the bloodstream make DDD85646 an exciting prospect for drug development, but an effective treatment needs to also work at a later stage of infection, when T. brucei has crossed into the central nervous system. Ideally, its selectivity for the T. brucei N-myristoyltransferase rather than the human form should be improved too. To enhance DD85646, it's important to understand how it works, and that's where the Structural Genomics Consortium helped out.

Inhibition assays had indicated that DDD85646 competes with the peptide substrate, but in the absence of a three-dimensional structure of N-myristoyltransferase the exact mechanism was not known. T. brucei N-myristoyltransferase would not crystallize but the highly similar Leishmania major form, which has 74% sequence identity with TbNMT and 94% identity within the peptide binding site, did.

The structure revealed that DDD85646 does indeed bind in the peptide substrate pocket of N-myristoyltransferase, but the structure showed something very interesting: the interactions between the compound and enzyme are mostly through water-mediated interactions rather than normal hydrogen bonding. Computer modeling of this complex is highly unlikely to have been able to predict this, illustrating the importance of obtaining the actual structure.

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References

  1. J. A. Frearson et al. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness.
    Nature 464, 728-732 (2010). doi:10.1038/nature08893

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