Alzheimer's disease, enzyme targets and drug discovery struggles: From natural products to drug prototypes

• Alzheimer's disease: the state of the drug discovery art.
• Acetylcholinesterase inhibitors in therapy.
• New enzymatic targets and inhibitors/enhancers.
• Secretases, sirtuins, caspases, glycogen synthase kinase-3.
• Autophagy and synaptogenesis inhibitors/enhancers.

Alzheimer's disease (AD) is an incapacitating neurodegenerative disease that slowly destroys brain cells. This disease progressively compromises both memory and cognition, culminating in a state of full dependence and dementia. Currently, AD is the main cause of dementia in the elderly and its prevalence in the developed world is increasing rapidly. Classic drugs, such as acetylcholinesterase inhibitors (AChEIs), fail to decline disease progression and display several side effects that reduce patient's adhesion to pharmacotherapy. The past decade has witnessed an increasing focus on the search for novel AChEIs and new putative enzymatic targets for AD, like β- and γ-secretases, sirtuins, caspase proteins and glycogen synthase kinase-3 (GSK-3). In addition, new mechanistic rationales for drug discovery in AD that include autophagy and synaptogenesis have been discovered. Herein, we describe the state-of-the-art of the development of recent enzymatic inhibitors and enhancers with therapeutic potential on the treatment of AD.

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