Peptide-based, irreversible inhibitors of γ-secretase activity

Piper, Siân C.; Amtul, Zareen; Galiñanes-Garcia, Laura; Howard, Victor; Ziani-Cherif, Chewki; McLendon, Chris; Rochette, Marjorie J.; Fauq, Abdul H.; Golde, Todd E.; Murphy, Michael P.

doi:10.1016/s0006-291x(03)00828-3

Cited by 4 publications

(3 citation statements)

References 47 publications

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“…Examples include EPNP (1,2-epoxy-3-(p-nitrophenoxy)propane), which is a well known unspecific irreversible inhibitor of aspartic proteases, [14][15][16] and cis-configured epoxides known to inhibit HIV-1 protease (Figure 2), [17][18][19][20][21][22] SIV protease, [23] and g-secretase known to be involved in Alzheimer's disease. [24] The cis-configuration is considered necessary for steric reasons ( Figure 3). …”

Section: Introductionmentioning

confidence: 99%

Cis‐Configured Aziridines Are New Pseudo‐Irreversible Dual‐Mode Inhibitors of Candida albicans Secreted Aspartic Protease 2

Degel¹,

Staib²,

Rohrer³

et al. 2008

ChemMedChem

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A series of cis-configured epoxides and aziridines containing hydrophobic moieties and amino acid esters were synthesized as new potential inhibitors of the secreted aspartic protease 2 (SAP2) of Candida albicans. Enzyme assays revealed the N-benzyl-3-phenyl-substituted aziridines 11 and 17 as the most potent inhibitors, with second-order inhibition rate constants (k(2)) between 56,000 and 121,000 M(-1) min(-1). The compounds were shown to be pseudo-irreversible dual-mode inhibitors: the intermediate esterified enzyme resulting from nucleophilic ring opening was hydrolyzed and yielded amino alcohols as transition-state-mimetic reversible inhibitors. The results of docking studies with the ring-closed aziridine forms of the inhibitors suggest binding modes mainly dominated by hydrophobic interactions with the S1, S1', S2, and S2' subsites of the protease, and docking studies with the processed amino alcohol forms predict additional hydrogen bonds of the new hydroxy group to the active site Asp residues. C. albicans growth assays showed the compounds to decrease SAP2-dependent growth while not affecting SAP2-independent growth.

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Section: Introductionmentioning

confidence: 99%

Cis‐Configured Aziridines Are New Pseudo‐Irreversible Dual‐Mode Inhibitors of Candida albicans Secreted Aspartic Protease 2

Degel¹,

Staib²,

Rohrer³

et al. 2008

ChemMedChem

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show abstract

“…However, one pharmacologically interesting feature resides in the fact that Aβ production from cells treated with peptide aldehydes recovers within the first 2 hours of washout as assayed by ELISA, indicating that this type of inhibitors are reversible. In contrast, use of their corresponding epoxides under the same conditions show an Aβ-recovering activity after 8 hours only, indicating that these epoxides constitute some irreversible γ-secretase inhibitors [142]. Based on these studies, compounds 24 and 25 (Fig.…”

Section: Collaboration Between Elan Pharmaceuticals and Elimentioning

confidence: 87%

Gamma-Secretase as a Pharmacological Target in Alzheimer Disease Research: When, Why and How?

Ziani-Cherif¹,

Mostefa‐Kara²,

Brixi-Gormat

2006

CPD

Self Cite

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Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (Abeta peptides) in the form of senile plaques as well as neurofibrillary tangles (NFTs) in the brain. In the amyloidogenic pathway, the amyloid-beta precursor protein (APP) is cleaved by beta-secretase first, followed by gamma-secretase cleavage producing therefore Abeta. This review summarizes the recent findings in the AD field and focuses on the different gamma-secretase inhibitors that have been developed as a therapeutic approach toward AD.

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“…All of these compounds also tested positive for Notch inhibition, either in vivo (Taniguchi et al 2002) or in vitro (Beck & Slack 2002). More recent inhibitors that are also known to modulate Notch include a hydroxyethylene peptidomimetic named L-685,458 (Shearman et al 2000, Sernee et al 2003 together with its homologous counterpart III-31-C (Li et al 2000, Esler et al 2002, the structurally related compounds D and E (Seiffert et al 2000, Beher et al 2001, CBAP (Beher et al 2001), LY411575 (Dovey et al 2001, Wong et al 2004), a dibenzazepine and benzodiazepine (Milano et al 2004), and a group of epoxides consisting of compounds IL, ILX, and KILX (Piper et al 2003). The abundance of pharmacological inhibitors of Notch signaling makes this another attractive target for inclusion in future in vitro differentiation protocols, as shown in Fig.…”

Section: The Notch Signaling Pathwaymentioning

confidence: 99%

Generating pancreatic β-cells from embryonic stem cells by manipulating signaling pathways

Tsaniras

Jones

2010

Journal of Endocrinology

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Type 1 diabetes results from an insufficiency of insulin production as a result of autoimmune destruction of the insulin-secreting pancreatic b-cells. It can be treated by transplantation of islets of Langerhans from human donors, but widespread application of this therapy is restricted by the scarcity of donor tissue. Generation of functional b-cells from embryonic stem (ES) cells in vitro could provide a source of an alternative graft material. Several ES cell differentiation protocols have reported the production of insulin-producing cells by mimicking the in vivo developmental stages of pancreatic organogenesis in which cells are transitioned through mesendoderm, definitive endoderm, foregut endoderm, pancreatic endoderm, and the endocrine precursor stage, until mature b-cells are obtained. These studies provide proof of concept that recapitulating pancreatic development in vitro offers a useful strategy for generating b-cells, but current differentiation protocols employ a bewildering variety of growth factors, mitogens, and pharmacological agents. In this review, we will attempt to clarify the functions of these agents in in vitro differentiation strategies by focusing on the intracellular signaling pathways through which they operate -phosphatidylinositol 3-kinase, transforming growth factor b, Wnt/b-catenin, Hedgehog, and Notch.

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Peptide-based, irreversible inhibitors of γ-secretase activity

Cited by 4 publications

References 47 publications

Cis‐Configured Aziridines Are New Pseudo‐Irreversible Dual‐Mode Inhibitors of Candida albicans Secreted Aspartic Protease 2

Cis‐Configured Aziridines Are New Pseudo‐Irreversible Dual‐Mode Inhibitors of Candida albicans Secreted Aspartic Protease 2

Gamma-Secretase as a Pharmacological Target in Alzheimer Disease Research: When, Why and How?

Generating pancreatic β-cells from embryonic stem cells by manipulating signaling pathways

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