Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein

Peuchmaur, Marine; Lacour, Marie-Agnès; Sévalle, Jean; Lisowski, Vincent; Touati-Jallabe, Youness; Rodier, Fabien; Martinez, Jean; Checler, Frédéric; Hernandez, Jean‐François

doi:10.1016/j.bmc.2012.11.045

Cited by 5 publications

(3 citation statements)

References 62 publications

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“…(b) We sought to investigate the structure-activity relationship between the inhibitory properties of C-7-substituted 4-chloroisocoumarins against CtHtrA. The scope of functional groups that have been introduced at this position is limited; the current literature reports only nitrogen-based substituents [18][19][20][21]. Thus, we developed new chemistry to expand the scope of functional groups that could be introduced at this position.…”

Section: Design and Synthesis Of 4-chloroisocoumarin Compoundsmentioning

confidence: 99%

4-Chloroisocoumarins as Chlamydial Protease Inhibitors and Anti-Chlamydial Agents

Phillips,

Huston,

McDonagh

et al. 2024

Molecules

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4-Chloroisocoumarin compounds have broad inhibitory properties against serine proteases. Here, we show that selected 3-alkoxy-4-chloroisocoumarins preferentially inhibit the activity of the conserved serine protease High-temperature requirement A of Chlamydia trachomatis. The synthesis of a new series of isocoumarin-based scaffolds has been developed, and their anti-chlamydial properties were investigated. The structure of the alkoxy substituent was found to influence the potency of the compounds against High-temperature requirement A, and modifications to the C-7 position of the 3-alkoxy-4-chloroisocoumarin structure attenuate anti-chlamydial properties.

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Section: Design and Synthesis Of 4-chloroisocoumarin Compoundsmentioning

confidence: 99%

4-Chloroisocoumarins as Chlamydial Protease Inhibitors and Anti-Chlamydial Agents

Phillips,

Huston,

McDonagh

et al. 2024

Molecules

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“…However, targeting γ-secretase must consider avoiding interference with the Notch signaling pathway, which is also digested by the enzyme. JLK isocoumarins [ 188 ] and certain NSAIDs have shown promise in reducing Aβ levels without impacting Notch signaling. Future medications should have sufficient potency, brain penetration, or selectivity to reduce brain Aβ levels while avoiding Notch-related toxicity.…”

Section: App-targeted Treatment Strategies In Admentioning

confidence: 99%

Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease

2023

Aging dis

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Decades of research have demonstrated an incontrovertible role of amyloid-β (Aβ) in the etiology of Alzheimer's disease (AD). However, the overemphasis on the pathological impacts of Aβ may obscure the role of its metabolic precursor, amyloid precursor protein (APP), as a significant hub in the occurrence and progression of AD. The complicated enzymatic processing, ubiquitous receptor-like properties, and abundant expression of APP in the brain, as well as its close links with systemic metabolism, mitochondrial function and neuroinflammation, imply that APP plays multifaceted roles in AD. In this review, we briefly describe the evolutionarily conserved biological characteristics of APP, including its structure, functions and enzymatic processing. We also discuss the possible involvement of APP and its enzymatic metabolites in AD, both detrimental and beneficial. Finally, we describe pharmacological agents or genetic approaches with the capability to reduce APP expression or inhibit its cellular internalization, which can ameliorate multiple aspects of AD pathologies and halt disease progression. These approaches provide a basis for further drug development to combat this terrible disease.

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“…The amyloid β-peptide (Aβ) is very likely a key element in the pathogenesis of Alzheimer's disease. 3,4 To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, our research group previously synthesized and evaluated a series of new modified isocoumarin analogues for their ability to inhibit cellular Aβ production. 4 We report herein on the structural characterization of one of them: the 7-amino-4-iodo-3-propyl-1H-isochromen-1-one (Fig.…”

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confidence: 99%