Novel compound series to treat African Trypanosomiasis

Type
Compound(s)

Novel compound series of phosphofructokinase allosteric inhibitors which show excellent efficacy in vitro against the parasite and in mouse models of the disease in vivo. Only a short treatment time is required as those compounds kill the parasite faster than any reported so far. The inhibitors are safe and show favorable pharmacokinetic properties including oral bio-availability and ability to cross the blood brain barrier. The well-characterized inhibitors of this novel
trypanosomiasis target have the potential to fill the unmet need for safe, cheap, easily administered drugs with short course for treatment for African trypanosomiasis.

OPPORTUNITY
African Trypanosomiasis is a neglected tropical disease caused by 2 subspecies Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. It develops in 2 distinct stages with the 1st, body stage, resulting in cold-like symptoms and the 2nd, central nervous system stage, characterised by severe neurological symptoms. It is fatal if left untreated. It is most prevalent in economically disadvantaged rural communities in Africa which have little health infrastructure. Existing treatments are only available intravenously or are subspecies specific. Moreover, they often have severe side effects, long treatment duration, drug resistance and are expensive. There is therefore an urgent need for new effective and easily administered drugs.

TECHNOLOGY OVERVIEW
Phosphofructokinase (PFK) is an enzyme in the glycolytic pathway which converts fructose 6-monophosphate to fructose 1, 6-biphosphate on the cascade of converting glucose to pyruvate and ATP. Glycolysis is the sole source of ATP for the bloodstream form of the parasite and blocking it has been shown to kill the parasite much faster than any other drug mechanism. These compounds target the allosteric binding site on the parasite PFK which locks the enzyme in an inactive state. This allosteric pocket is unique to parasite PFK, therefore human phosphofructokinase is completely unaffected by the compounds minimising side effects. The drugs have been extensively characterised both in vitro and in vivo in terms of selectivity, potency and pharmacokinetics and show very favourable properties. Moreover, Trypanosoma brucei’s phosphofructokinase enzyme - compounds interaction have been very well studied by numerous crystal structures which would allow them to be easily modified to further improve properties.

Names of infectious Organisms: Trypanosoma brucei
Vector: Tsetse Flies
Human Target Organs: Blood /Lymph system in phase 1: CNS in phase 2
Mechanism of Action: Inhibition of key enzyme in the glycolytic pathway of the parasite
Molecular or Cellular Target Names: Phosphofructokinase (PFK)

BENEFITS
 Novel validated target, well characterised mechanism of action and excellent structure-activity relationship
 Compounds effective against both subspecies of the parasite and both stages of the disease
 Orally bioavailable and able to cross the blood brain barrier in favourable proportions
 Safe and effective in a mouse model with very short treatment duration (1-2 days)
 Very fast time to completely kill the parasite (minutes vs days for other drug classes)
 Can be used in combination with current medicines as they have a different mechanism of action
Sub-micro- molar activity against enzyme target PFK
Selectivity for trypanosomal over human PFK
Rapid and effective growth inhibition activity against parasites that cause HAT - Trypanosoma brucei rhodesiense and gambiense
In vivo efficacy in 2 mouse models of trypanosomiasis after single dose
Blood Brain Barrier penetration
Favourable ADME profile
Confirmed mechanism of action (ie enzyme inhibition correlates with level of parasite killing)
Known SAR, X-ray crystal structures of compounds bound to tPFK available to guide further rapid optimisation

PUBLICATION
ACS Med. Chem. Lett. 2014, 5, 12−17
Biophys J 2015, 109, 1149-1156

Disease
Human African trypanosomiasis (HAT)
Research areas
Drug
Condition of use

Collaboration, co-development and licensing

IP information

UK patent application protecting the lead series.
Priority date 01/12/2017