Fenchylamine Sulfonamide Inhibitors of Amyloid β Peptide Production by the γ-Secretase Proteolytic Pathway:  Potential Small-Molecule Therapeutic Agents for the Treatment of Alzheimer's Disease

Rishton, Gilbert M.; Retz, Daniel M.; Tempest, Paul; Novotny, James F.; Kahn, Steve; Treanor, James; Lile, Jack D.; Citron, Martin

doi:10.1021/jm990622z

Cited by 68 publications

(41 citation statements)

References 8 publications

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“…These mapping studies are important, in identifying which region of the peptide interacts with the ligand, and determine whether the hydrophobic segment of A␤ is involved, which is responsible for the ␤-sheet intermolecular conformation in aqueous solutions and, consequently, for the neurotoxicity of the peptide. Trypsin cleaves the peptide in almost equal segments of 11-12 residues, except from the first [1][2][3][4][5] fragment. Glu-C cleaves the peptide in fragments of various lengths, but in between the three first fragments derived from the tryptic digestion (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…Digestion with trypsin yielded the four expected A␤ fragments: [1][2][3][4][5], [6 -16], [17][18][19][20][21][22][23][24][25][26][27][28], and [29 -40] following cleavage after arginine (R) or lysine (K) residues (Table 2), as well as partially cleaved fragments ( Table 3). The soft ESI ionization also enabled the detection of noncovalent interactions between sequential and nonsequential fragments.…”

Section: Resultsmentioning

confidence: 99%

“…It is the central component of the senile plaques in Alzheimer disease (AD) brain [1] and its aggregational properties depend on both the peptide concentration and conformation, as well as on the solution conditions and pH [2,3]. It has been reported that reduction of the A␤ production, by controlling the cleavage of the larger transmembrane amyloid precursor protein (APP), or inhibition of its aggregation by using small molecules, which may interact noncovalently with A␤ and stabilize its structure, could serve as preventive or therapeutic approaches against AD [4]. In general, interruption of noncovalent interactions between protein and peptides, or even more between proteins/peptides and ligands can cause abnormalities, which often lead to diseases [5].…”

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confidence: 99%

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Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

Bazoti

Bergquist

Markides

et al. 2008

J. Am. Soc. Mass Spectrom.

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Abnormal accumulation and aggregation of amyloid-␤-peptide (A␤) eventually lead to the formation and cerebral deposition of amyloid plaques, the major pathological hallmark in Alzheimer's disease (AD). Oleuropein (OE), an Olea europaea L. derived polyphenol, exhibits a broad range of pharmacological properties, such as antioxidant, anti-inflammatory, and antiatherogenic, which could serve as combative mechanisms against several reported pathways involved in the pathophysiology of AD. The reported noncovalent interaction between A␤ and OE could imply a potential antiamyloidogenic role of the latter on the former via stabilization of its structure and prevention of the adaptation of a toxic ␤-sheet conformation. The established ␤-sheet conformation of the A␤ hydrophobic carboxy-terminal region and the dependence of its toxicity and aggregational propensity on its secondary structure make the determination of the binding site between A␤ and OE highly important for assessing the role of the interaction. In this study, two different proteolytic digestion protocols, in conjunction with high-sensitivity electrospray ionization mass spectrometric analysis of the resulting peptide fragments, were used to determine the noncovalent binding site of OE on A␤ and revealed the critical regions for the interaction. and its aggregational properties depend on both the peptide concentration and conformation, as well as on the solution conditions and pH [2,3]. It has been reported that reduction of the A␤ production, by controlling the cleavage of the larger transmembrane amyloid precursor protein (APP), or inhibition of its aggregation by using small molecules, which may interact noncovalently with A␤ and stabilize its structure, could serve as preventive or therapeutic approaches against AD [4]. In general, interruption of noncovalent interactions between protein and peptides, or even more between proteins/peptides and ligands can cause abnormalities, which often lead to diseases [5]. One interaction of this kind has been established between the Olea europaea derived bioactive compound, oleuropein (OE), and A␤ by means of electrospray ionization mass spectrometry (ESI-MS) [6]. This interaction could prove potent in inhibiting its aggregation.OE is a polyphenol extracted from the fruits and leaves of Olea europaea L. and possesses a wide range of pharmacological properties, such as antioxidant [7][8][9], anti-inflammatory [10, 11], antiatherogenic [12-14], antibacterial [15][16][17], and anticancer [18,19]. Moreover, OE and its metabolites have been shown to be potent against contemporary diseases, such as HIV [20,21] and osteoporosis [22,23]. Interestingly, in vitro [24] and epidemiological [25] studies demonstrated the positive impact of polyphenols on the onset of age-related disorders, such as dementia [26,27].It is regarded that the pathophysiology of AD is tangled and many theories have been proposed to illumine its mechanism. Free radical reactions and oxidative stress [28,29], as well as unregulated immune response [30,3...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

Bazoti

Bergquist

Markides

et al. 2008

J. Am. Soc. Mass Spectrom.

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“…The MLK inhibitor CEP-11004 was a generous gift from Cephalon Inc. (West Chester, USA). 26 The g-secretase inhibitor 1-(S)-endo-N-(1,3,3)-trimethylbicyclo[2.2.1]hept-2-yl)-4-fluorophenyl sulfonamide 21 was from Merck Biosciences (Schwalbach, Germany). All other biochemicals and chemicals came in analytical grade purity from Roche Diagnostics (Mannheim, Germany) or Roth (Karlsruhe, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…In comparison to APPwtoverexpressing cells, expression of SPARC/osteonectin was significantly enhanced in cells overexpressing APPsw ( Figure 1b). A fenchylamine sulfonamide g-secretase inhibitor 21 had no discernible effect in any of the cell lines (Figure 1b), indicating that APP processing by a-secretase might be required for the APP-mediated inhibition of SPARC/ osteonectin expression. We subsequently investigated whether APP exerts a regulatory effect on the JNK signalling pathway.…”

Section: Introductionmentioning

confidence: 99%

Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway

et al. 2004

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The amyloid precursor protein (APP) has been suggested to regulate gene expression. GeneChip s analysis and in vitro kinase assays revealed potent APP-dependent repression of c-Jun, its target gene SPARC and reduced basal c-Jun Nterminal kinase (JNK) activity in PC12 cells overexpressing APP. UV-induced activation of the JNK signalling pathway and subsequent apoptosis were likewise reduced by APP and this effect could be mimicked by the indirect JNK inhibitor CEP-11004. Treatment with a c-secretase inhibitor did not affect APP-mediated downmodulation of the JNK signalling pathway, suggesting that the effects might be mediated via asecretase processing of APP. In support of these data, overexpression of the Swedish mutant of APP did not inhibit SPARC expression, UV-induced JNK activation and cell death. Our data suggest an important physiological role of APP and a-secretase activity in the control of JNK/c-Jun signalling, target gene expression and cell death activation in response to cytotoxic stress.

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Alzheimer's Disease: Search for Therapeutics

Rzeszotarski

2003

Burger's Medicinal Chemistry and Drug Discovery

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Over the next 50 years the incidence of Alzheimer's disease (AD) in the United States is expected to triple from about 420,000 new cases in 1999 to 1.32 million per year. Assuming no successful intervention, the prevalence of AD could be expected to rise over the next 50 years by a factor of about 3.7–8.94 million, with the range of 4.55–15.81 million in the United States alone. With the exception of early‐onset familial AD (FAD) the disease is age correlated and its incidence grows exponentially with age. In part, because of their increased longevity, women represent and will continue to represent the majority (68% in 1997) of the affected population. If one adds the year 2000 U.S. census figures to the population of the European Union (EU‐15) and Japan, the prevalence of AD in “the major pharmaceutical markets” for that year could be estimated as close to 8.7 million. The as yet uncertain etiology of AD precluded the attempts to prevent its onset. Cholesterol, immune response, and oxidation damage appear to precede the deposition of amyloid β‐peptides (Aβ) and formation of senile (neuritic) plaques and intracellular neurofibrillary tangles. This is why the epidemiology and in vitro studies fail to point to right therapies. The statins, antioxidants, anti‐inflammatory agents, estrogens, or testosterone may belong to preventive measures but may fail as therapeutics. At present, no agent is available to arrest, delay, or reverse the progress of the disease.

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Fenchylamine Sulfonamide Inhibitors of Amyloid β Peptide Production by the γ-Secretase Proteolytic Pathway: Potential Small-Molecule Therapeutic Agents for the Treatment of Alzheimer's Disease

Cited by 68 publications

References 8 publications

Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway

Alzheimer's Disease: Search for Therapeutics

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