Piperidine Acetic Acid Based γ-Secretase Modulators Directly Bind to Presenilin-1

Crump, Christina J.; Fish, Benjamin A.; Castro, Suita V.; Chau, De-Ming; Gertsik, Natalya; Ahn, Kwangwook; Stiff, Cory M.; Pozdnyakov, Nikolay; Bales, Kelly R.; Johnson, Douglas S.; Li, Yueming

doi:10.1021/cn200098p

Cited by 59 publications

(95 citation statements)

References 41 publications

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“…S7b). GSMs have also been shown to target PS1-NTF 9,22,29 , supporting the hypothesis that these compounds could bind at the interface between APP-C99 and the substrate-docking site of g-secretase. Moreover, the region between g-and e-sites on APP-CTF has been proposed to be a binding domain for PS1-NTF 30 , and peptides mimicking this domain can selectively block Ab production, sparing Notch processing 31 .…”

Section: Discussionmentioning

confidence: 57%

“…A subset of non-steroidal antiinflammatory drugs (NSAIDs) were the first Notch-sparing small molecules shown to selectively lower Ab42 and subsequently raise Ab38 both in vitro and in vivo 19,20 . These g-secretase modulators (GSMs) were initially shown to bind to APP, although some more recent studies demonstrated that they also can target g-secretase 21,22 . Although the precise molecular mechanism of action remains poorly understood, a number of these molecules have advanced to clinical trials 23 .…”

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confidence: 99%

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Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

et al. 2013

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Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical g-secretase modulators affect the processing of APP by the g-secretase complex and the production of the amyloid-beta peptide Ab42, the accumulation of which is considered causative of Alzheimer's disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer's disease affect both g-and e-cleavage sites, by raising the Ab42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to g-secretase modulators, which shift Ab42 production towards the shorter Ab38, but unequivocally spare the e-site and APP-and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer's disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its g-site, modifying at the same time, the solvation of the e-site.

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Section: Discussionmentioning

confidence: 57%

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confidence: 99%

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

et al. 2013

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“…E2012 (US2006/0004013), GSM-1 (WO2006/043064), GSM-5 (27), BMS-708,163 (30), L-685,458 (L458), L-682,679 (L679) (31), and L458-BPyne (32) were prepared according to published methods. The helical peptide inhibitor that targets the substrate docking site (pep11, Boc-…”

Section: Methodsmentioning

confidence: 99%

“…anistically modulate the genesis of A␤ peptides, we generated novel GSM-based photoaffinity probes (27). Here, we describe the design and synthesis of a clickable photoprobe based on the imidazole GSM E2012 (Fig.…”

Section: Design Of Potent Clickable Photoaffinity Probe Based On E201mentioning

confidence: 99%

“…However, this proposal has been disputed because these NSAID-based GSMs are prone to form aggregates that can bind nonspecifically to A␤ (26). In contrast, we and others have reported that photoaffinity probes from the piperidine acetic acid class of GSMs specifically label the N-terminal fragment of presenilin 1 (PS1-NTF) (27)(28)(29). The exact target of the imidazole GSM series is also controversial.…”

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confidence: 99%

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γ-Secretase Modulator (GSM) Photoaffinity Probes Reveal Distinct Allosteric Binding Sites on Presenilin

Pozdnyakov

Murrey

Crump

et al. 2013

Journal of Biological Chemistry

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116

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Background: Potent GSMs have been identified that lower A␤42; however, the mechanism of modulation is not well understood. Results:The photoaffinity probe E2012-BPyne specifically labels PS1-NTF at a unique site. Conclusion: Acid and imidazole GSMs bind to distinct sites on PS1-NTF and are differentially affected by L458. Significance: Our results provide evidence for multiple binding sites within ␥-secretase that confer specific modulatory effects.

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Understanding familial Alzheimer's disease: The fit‐stay‐trim mechanism of γ‐secretase

Mehra

Kepp

2021

WIREs Comput Mol Sci

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Understanding Alzheimer's disease is a central challenge of the 21st century, as the disease affects tens of millions of people and kills a million people each year, with current drugs having modest effect. This article reviews how computational science integrating new cryo‐electron microscopy structures and biochemical and clinical data has led to a causative model of familial Alzheimer's disease (fAD). The model's basis is open and compact conformational states of the membrane protease γ‐secretase, controlled by transmembrane helix “fingers” that hold the substrate either tightly or loosely. The two states are in thermal equilibrium and lead to different amounts of long and short Aβ peptides, explaining the much‐debated Aβ42/Aβ40 ratio. Pathogenic mutations shift the equilibrium toward the open state by reducing the stability and hydrophobic packing of the enzyme‐substrate complex, which increases toxic Aβ42 and other longer peptide forms compared with Aβ40. In contrast, drugs that selectively target longer, pathogenic Aβ peptides should preferentially stabilize the compact state to reverse this tendency. The model may explain how inherited mutations cause fAD and provides a molecular roadmap for the development of γ‐secretase modulators, one of the most promising causative treatment strategies in current Alzheimer research. In summary, we showcase the power of modern multiscale computational science in integrating biochemical, protein‐structural, and clinical data to elucidate complex disease mechanisms. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Data Science > Chemoinformatics

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Piperidine Acetic Acid Based γ-Secretase Modulators Directly Bind to Presenilin-1

Cited by 59 publications

References 41 publications

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

γ-Secretase Modulator (GSM) Photoaffinity Probes Reveal Distinct Allosteric Binding Sites on Presenilin

Understanding familial Alzheimer's disease: The fit‐stay‐trim mechanism of γ‐secretase

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