The disclosure of potential drugs’ activity is related to the affinity for a biological target which is reflected in the ligand binding constant for the target biopolymer. Drug activity is therefore mediated by different types of interactions with specific biological targets and the esteem of these interactions may elucidate the drug mechanism of action to improve activity and specificity. In the case of Alzheimer’s disease (AD), the most common form of dementia in adults, acetylcholinesterase (AChE) has become the target for the development of new drugs since the discovery of the cholinergic deficit in the central nervous system. AChE inhibitors, blocking the acetylcholine catalysis, promote the cholinergic function, improving the cognitive deficit. On the other hand, other non cholinergic role of AChE in the AD has been discovered: some evidences suggest that AChE peripheral binding site may play a key role in the development of senile plaques, accelerating b-amyloid peptide (Ab) deposition. In order to develop new AChE inhibitors as new drugs capable not only of reducing the symptoms, but also of preventing or delaying the death of the cholinergic neurons, the capacity of blocking the amyloidogenic effect of AChE need to be tested. Therefore, peripheral and dual binding AChE inhibitors might represent a new therapeutic option, as these compounds should be able, both to contrast the cognitive deficiency and to avoid Ab aggregation. Here we report the development of purposely designed integrated methodologies to define the multifunctional activity profile for new AD drug discovery. Firstly, a Human Recombinant AChE monolithic micro-IMER (immobilized enzyme reactor) has been developed for on-line automated HTP (high throughput) HPLC inhibition studies (IC50 and mechanism of inhibition); secondly, fluorometric and circular dichroism methods were optimised for monitoring the inhibition of AChE induced Ab fibril formation and the inhibition of spontaneous Ab aggregation. By the application of these integrated approaches, a new lead as the prototype of a new class of compounds for AD treatment was discovered.

INTEGRATED ANALYTICAL APPROACHES FOR ALZHEIMER’S DISEASE NEW DRUG DISCOVERY

BARTOLINI, MANUELA;BERTUCCI, CARLO;CAVRINI, VANNI;ANDRISANO, VINCENZA
2004

Abstract

The disclosure of potential drugs’ activity is related to the affinity for a biological target which is reflected in the ligand binding constant for the target biopolymer. Drug activity is therefore mediated by different types of interactions with specific biological targets and the esteem of these interactions may elucidate the drug mechanism of action to improve activity and specificity. In the case of Alzheimer’s disease (AD), the most common form of dementia in adults, acetylcholinesterase (AChE) has become the target for the development of new drugs since the discovery of the cholinergic deficit in the central nervous system. AChE inhibitors, blocking the acetylcholine catalysis, promote the cholinergic function, improving the cognitive deficit. On the other hand, other non cholinergic role of AChE in the AD has been discovered: some evidences suggest that AChE peripheral binding site may play a key role in the development of senile plaques, accelerating b-amyloid peptide (Ab) deposition. In order to develop new AChE inhibitors as new drugs capable not only of reducing the symptoms, but also of preventing or delaying the death of the cholinergic neurons, the capacity of blocking the amyloidogenic effect of AChE need to be tested. Therefore, peripheral and dual binding AChE inhibitors might represent a new therapeutic option, as these compounds should be able, both to contrast the cognitive deficiency and to avoid Ab aggregation. Here we report the development of purposely designed integrated methodologies to define the multifunctional activity profile for new AD drug discovery. Firstly, a Human Recombinant AChE monolithic micro-IMER (immobilized enzyme reactor) has been developed for on-line automated HTP (high throughput) HPLC inhibition studies (IC50 and mechanism of inhibition); secondly, fluorometric and circular dichroism methods were optimised for monitoring the inhibition of AChE induced Ab fibril formation and the inhibition of spontaneous Ab aggregation. By the application of these integrated approaches, a new lead as the prototype of a new class of compounds for AD treatment was discovered.
15th International Symposium on Pharmaceutical and Biomedical Analysis, PBA2004
64
64
M. Bartolini; C. Bertucci; V. Cavrini; V. Andrisano.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/13410
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