title: Alzheimer's disease, enzyme targets and drug discovery struggles: from natural products to drug prototypes.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Sciences of Porto, Porto, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Silva
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Sciences of Porto, Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Reis
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Sciences of Porto, Porto, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Teixeira
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Sciences of Porto, Porto, Portugal. Electronic address: fborges@fc.up.pt.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D001688:Biological Products / Q000627:therapeutic use*; D055808:Drug Discovery; D006801:Humans
chemical_list: D001688:Biological Products
keywords: Acetylcholinesterase and inhibitors; Alzheimer's disease; Autophagy enhancers; Caspases and inhibitors; Glycogen synthase kinase-3 and inhibitors; Sirtuins and inhibitors; Synaptogenesis enhancers; β- and γ-secretases and inhibitors