Reference #: 01401
The University of South Carolina is offering licensing opportunities for Monosaccharide Amine and 3-Nitro-2-Phenyl-2H-Chromene Based Inhibitors of Glucose Kinases
Background:
When a kissing bug bites a human, they can be infected with a Kinetoplastid parasite such as Trypanosoma cruzi (T. cruzi). A need exists for new drugs that strongly bind to drug targets found in these parasites. Such a need includes inhibitors of the glucose kinase enzymes, which include hexokinase and/or glucokinase. These enzymes produce the product glucose-6phosphate (G6P), which acts as the starting substrate for the PPP. A need also exists for such inhibitors that will provide an alternative to the clinically used drugs at the present time. T. cruzi, Trypanosoma brucei (T. brucei), and Leishmania spp. utilize and depend on metabolic pathways for survival. An example of a metabolic pathway is the pentose phosphate pathway (PPP) for the production of the reducing agent NADPH and also for nucleic acid and nucleotide biosynthesis. The PPP is essential for these organisms and obstruction of the pathway leads to apoptosis. Obstruction could be caused by inhibition of the enzyme glucose 6-phosphate dehydrogenase by use of a drug. In order to operate successfully as a therapeutic drug, an inhibitor should selectively bind to the parasite homologue drug-target and avoid cross-reactivity with the patient’s homologous enzyme (e.g., bind to the human homologous enzyme with much less strength or none at all), giving rise to a good parasite selectively ratio.
Invention Description:
Kinetoplastid parasites, such as Trypanosoma cruzi (T. cruzi), Trypanosoma brucei (T. brucei), and Leishmania spp., utilize and depend on the pentose phosphate pathway (PPP) for the reducing agent NADPH and also rely on the PPP for support for nucleic acid and nucleotide biosynthesis. These same parasites also depend on the glycolytic pathway for energy production. Glycolysis and the PPP are essential for these organisms and glucose kinases (hexokinase and glucokinase) are at the nodal point between both glycolysis and the PPP. The obstruction of the pathways will lead to cell death and can be caused by inhibition (using an inhibitor/drug) of the glucose kinase enzymes. In order to create a therapeutic drug, an inhibitor would need to selectively bind with the parasite homologue and avoid cross reactivity with the human homologue (bind weaker or not bind at all), giving rise to a good selectively ratio. The compounds for this patent are strong inhibitors of T. cruzi glucose kinases.
Potential Applications:
T. cruzi is the causative agent for Chagas’ disease, and benznidazole and nifurtimox are the two main clinically available treatments available in Latin America. These drugs have the potential for resistance because they were developed over 35 years ago and alternative drugs have not emerged. T. brucei is the causative agent for human African sleeping sickness and various drugs are available, such as pentamidine, suramin, eflornithine, and melarsoprol. Leishmania spp. are protozoan parasites causing Leishmaniasis and medical intervention requires treatment such as pentavalent antimony-based medicines, or more expensive treatments such as amphotericin B, miltefosine, or paramomycin. The drugs for these kinetoplasid diseases all require substantial improvements in their tolerability, safety, and efficacy. A need exists for new drugs that strongly bind to drug targets found in these parasites. Such a need includes inhibitors of the glucose kinase enzymes, hexokinase and glucokinase. The inhibitors covered in this patent are to provide alternatives to the clinically used drugs
Advantages and Benefits:
These are newly identified inhibitors of glucose kinases, which are found in protozoan parasites and other pathogenic organisms. The drugs proposed in this patent may serve as viable substitutes for the currently used drugs in the clinic, pending in vitro parasite studies and mouse infectivity studies.