An anti-inflammatory compound has shown therapeutic benefits in many in-vivo and in-vitro diseases
The University of Exeter has developed novel anti-inflammatory, cytoprotectant compounds which selectively target mitochondria.
An anti-inflammatory compound has shown therapeutic benefits in many disease models.
Mitochondria are key intracellular organelles regulating cellular metabolism, cell death and survival, inflammatory signalling (e.g. inflammasome) and blood vessel tone.
Impairment of mitochondrial function is a key pathological finding in many diseases (e.g. arthritis, hypertension, sepsis, myocardial infarction, diabetes).
The compounds work by affecting the targeted slow release of hydrogen sulfide.
Perturbed synthesis of endogenous gasomediator hydrogen sulfide (H2S) has been implicated by many researchers in mitochondrial impairment.
These molecules offer enormous potential as therapeutics for cardiovascular, neurodegenerative and inflammatory disease.
- These are small molecule compounds that meet good drug-like criteria.
- Compounds selectively target and concentrate within mitochondria allowing for minimal loading dose.
- Anti-inflammatory: Inhibit pro-inflammatory signalling in the picomolar-nanomolar range whether given therapeutically as well as prophylactically.
- Cytoprotection: prevents pro-inflammatory and oxidative insult induced cell death in the nM range by preserving mitochondrial function and inhibition of caspase activity.
- Vasodilatory: sustained blood pressure reduction in spontaneously hypertensive rats by inhibition of Ca2+ channel activity and prolonged opening of Cl- conductance channels in the nM range..
- Relevance to acute (e.g. sepsis) and chronic (e.g. rheumatoid arthritis, colitis, asthma, COPD, cystic fibrosis etc.) inflammatory conditions, cardiovascular and renal disease (e.g. hypertension, atherosclerosis, myocardial infarction, heart failure etc.) and other diseases with impaired mitochondrial function (e.g. osteoarthritis, osteoporosis, diabetes, obesity, cancer).
The invention consists of small molecule mitochondria-targeted H2S donors (MTHD) that generate H2S in a slow and sustained manner that is more akin to endogenous H2S release.
The inventors have shown that MTHDs have more than 1,000 fold more potency over non-targeted H2S donors at inducing vasorelaxation in isolated blood vessels and sustained lowering of blood pressure and heart rate in spontaneously hypertensive rats in vivo.
In isolated human monocytes and airway smooth muscle cells, MTHDs inhibit the synthesis of pro-inflammatory mediators such as IL-6 and IL-8 in the sub pM-nM range and inhibit the activation and activity of the inflammasome and tumour necrosis factor-α converting enzyme (TACE).
In human microvascular endothelial cells, MTHDs prevent cell death induced by a variety of pro-oxidant mediators in the nM range by preserving mitochondrial function, conserving ATP and promoting cellular bioenergetics, reducing oxidative stress and inhibiting caspase activation and activity.
Perturbed synthesis of H2S is reported in many human conditions and animal models of human disease. Targeting mitochondria with H2S and preserving mitochondrial and cellular integrity can provide an effective means for decreasing cell death and inflammation in a variety of inflammatory, degenerative, neurodegenerative and cardiovascular pathologies.
- Acute and chronic inflammation: arthritis, colitis, sepsis, burn injury, pancreatitis, dermatitis.
- Cardiovascular: hypertension, myocardial infarction, cardiac arrest/heart failure, ischaemia-reperfusion injury, renal failure, atherosclerosis, diabetic angiopathy.
- Lung: COPD, asthma, cystic fibrosis.
- Metabolic: diabetes, obesity, metabolic syndrome.
- Bone and joint: osteoporosis, osteoarthritis.
- Neurological: neurodegenerative diseases (e.g. Alzheimer’s, Parkinson’s), stroke, epilepsy.
The compounds created here are covered by patent application PCT/GB2012/052424
The University is keen to discuss potential partnerships with a view to collaborations or commercial licensing opportunities