The goals for the Neglected Diseases Program:
- study African sleeping sickness,
- study Leishmaniasis,
- study Chagas diseases,
- study Tuberculosis,
- study Malaria.
Why study the Human African Trypanosomiasis (HAT)?
- approximately 100% fatal if not treated,
- diagnostics are inadequate,
- current existing drugs are inadequate,
- can carry siRNA studies for target validadtion.
How about the product profile?
- needs to show acceptable toxicity, i.e., <1% drug related mortality
- preferred drug related mortality would b e<0.1%,
- pharmaceutical need to show 100% pathogen mortality.
What are the hit discoveries strategies?
- a two stringed strategy:
1) to genetically validate molecular targets,
2) and a phenotypic screening.
What about the portfolio of halted HAT projects?
The idea is target assessment > assay development > hit discovery... and so on.
The accompished product N-Myristoyltrabsferase (NMT):
- it is a ubiquitous and essential enzyme in all eukaryotic cells,
- NMT catalyses the attachment of myristate onto the N-terminal glycene of potentially over 60 peptides.
NMT is required for T. brucei survival:
- they've realised that after an interference siRNA study, in vivo.
About optimising the product:
- they investigated SAR for each moiety,
the principal initial aim was to identify the best molecule possible and work the aromatic region to reach a more stable one,
- they purchased approximately 30 commercially available analogues.
Rigidified amine-bearing compounds:
- introduction of conformational restriction defines optimal amine orientation.
- NMT inhibition correlates with activity in trypanosomes in vitro,
- the compounds act on NMT in situ,
- the central nervous system (CNS) was taken as a key issue with a CNS penetration of B:B ratio of <0.1,
And where are they at the moment?
- working the NMT inhibitors,
- the target is validated through to activity in mouse model of HAT,
- good understanding of drivers of inhibitor potency
- ... etc etc etc.
Figure 1 taken from Structure of a ternary complex of N-myristoyl transferase (NMT) bound to N-myristoyl-CoA and a peptide analog, [http://people.cryst.bbk.ac.uk/~ubcg54a/nmt1.html), last access on the 17th of May 2012.
Figure 2 taken from Parasites and Health, [http://www.dpd.cdc.gov/dpdx/html/frames/s-z/trypanosomiasisafrican/body_trypanosomiasisafrican_page1.htm], last access on the 17th of May 2012, last update unknown.