Enzyme-like drugs against Alzheimer's disease
The growing incidence and socioeconomic burden of Alzheimer's disease emphasises the need for novel therapies. Medium sized peptide-transition metal complexes can act as enzymes and perform proteolysis of pathogen substrates, overcoming many of the difficulties encountered with present drugs. The scope of the EU-funded ORGANOZYMES (Nanocatalytic drugs towards Alzheimer's disease) project was to implement these so called organozymes for the hydrolysis of peptide bonds in the Alzheimer's disease-related peptide amyloid beta (Aβ 1-42). Towards this goal, scientists designed catalyst libraries based on peptido-carbenes to obtain cleavage and selectivity against the plaque-forming Aβ 1-42 substrate. Overall, 300 000 compounds were generated with dipeptide mimetic carbene precursors incorporated into peptides chains that also contained metal atoms such as palladium, iron or zinc. Screening of these compounds was based on fluorescence emission following the catalysis of the Alzheimer core sequence presented on single fluorescent beads. Approximately 60 hits showed clear evidence of consensus and specific recognition of the pathogenic Aβ substrate. Although elucidation of the cleavage mechanism and conditions are pending, the ORGANOZYMES project demonstrated the capacity of artificial peptide catalysts to act as enzymes. The specific recognition and cleavage of the Alzheimer substrate will prevent the formation of Alzheimer fibrils that are characteristic of plaques observed in the brain of patients. The developed methodology will pave the way for new approaches towards other incurable diseases.
Keywords
Enzyme, Alzheimer's disease, ORGANOZYMES, amyloid beta, peptide-carbene
