Inhibition and Modulation of γ-Secretase for Alzheimer's Disease

Wolfe, Michael S.

doi:10.1016/j.nurt.2008.05.010

Cited by 130 publications

(117 citation statements)

References 75 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Perhaps most promisingly, there exists an extensive drug-discovery repositioning opportunity for potential SPP inhibitors in existing chemical libraries from pharmaceutical companies. PS and SPPs are part of the A22-family integral membrane aspartyl proteases; it is therefore likely that there exist numerous potent PfSPP drug-like inhibitors in PS-directed chemical libraries, reducing cost barriers for development (39)(40)(41). Indeed, LY-411575 was a product of previous a PS drug-discovery effort.…”

Section: Discussionmentioning

confidence: 99%

Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design

Harbut

Patel

Yeung

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

110

View full text Add to dashboard Cite

Early secretory and endoplasmic reticulum (ER)-localized proteins that are terminally misfolded or misassembled are degraded by a ubiquitin-and proteasome-mediated process known as ER-associated degradation (ERAD). Protozoan pathogens, including the causative agents of malaria, toxoplasmosis, trypanosomiasis, and leishmaniasis, contain a minimal ERAD network relative to higher eukaryotic cells, and, because of this, we observe that the malaria parasite Plasmodium falciparum is highly sensitive to the inhibition of components of this protein quality control system. Inhibitors that specifically target a putative protease component of ERAD, signal peptide peptidase (SPP), have high selectivity and potency for P. falciparum. By using a variety of methodologies, we validate that SPP inhibitors target P. falciparum SPP in parasites, disrupt the protein's ability to facilitate degradation of unstable proteins, and inhibit its proteolytic activity. These compounds also show low nanomolar activity against liver-stage malaria parasites and are also equipotent against a panel of pathogenic protozoan parasites. Collectively, these data suggest ER quality control as a vulnerability of protozoan parasites, and that SPP inhibition may represent a suitable transmission blocking antimalarial strategy and potential panprotozoan drug target.intramembrane proteolysis | small molecule | target validation

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design

Harbut

Patel

Yeung

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

110

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that A␤ levels in brains can be reduced by decreasing ␥-secretase activity (reviewed in Ref. 41). Therefore, an exact understanding of the mechanism by which cellular ␥-secretase activity is negatively regulated might provide the basis for a novel therapeutic strategy for AD other than development of direct inhibitors of ␥-secretase.…”

Section: Discussionmentioning

confidence: 99%

Human CRB2 Inhibits γ-Secretase Cleavage of Amyloid Precursor Protein by Binding to the Presenilin Complex

Hasegawa

Matsuo

Araki

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Drosophila Crumbs has been reported to attenuate Notch signaling by inhibition of ␥-secretase cleavage at the wing margins. ␥-Secretase is an intramembrane protease that is responsible for the generation of amyloid-␤ (A␤) peptides from the ␤-amyloid precursor protein (APP). Here, we re-examined ␥-secretase inhibition by human CRB2, which is the most abundant Crumbs ortholog in the brain. Transfected CRB2 inhibited proteolytic production of A␤ and APP intracellular domains from APP C-terminal fragments in HEK293 and SH-SY5Y cells. Conversely, knockdown of endogenous CRB2 increased ␥-secretase cleavage products in SH-SY5Y cells. CRB2 inhibition of ␥-cleavage was also detected in cell-free assays. CRB2 interacted with the ␥-secretase complex, but was not a competitive substrate for ␥-cleavage. The transmembrane domain of CRB2 was indispensable for inhibition of A␤ generation and mediated CRB2 binding with the ␥-secretase complex. In addition, the cytoplasmic domain appeared to play a supportive role in ␥-secretase inhibition, whereas mutational disruption of the two protein-binding motifs involved in the formation of cell adhesion complexes did not affect ␥-secretase inhibition. Co-overexpression of presenilin-1 or APH-1 abrogated ␥-secretase inhibition probably through prevention of the incorporation of CRB2 into the ␥-secretase complex. Our results suggest that CRB2 functions as an inhibitory binding protein that is involved in the formation of a mature but inactive pool of the ␥-secretase complex.

show abstract

“…While there are currently no drugs in clinical use that target these mechanisms, many putative disease-modifying inhibitors are under active development and some have shown in vivo efficacy in mouse models and in clinical trials. [4][5][6][7][8] One of the most notable examples is Neurochem's Alzhemed (tramiprosate) that was developed to prevent amyloid formation and deposition in the brain, and thus modify the course of AD. Unfortunately, despite Alzhemed's promise in Phase II clinical trials, the recent U.S.…”

Section: Introductionmentioning

confidence: 99%

Discovery of amyloid‐beta aggregation inhibitors using an engineered assay for intracellular protein folding and solubility

Lee

Chang

et al. 2009

Protein Science

View full text Add to dashboard Cite

Genetic and biochemical studies suggest that Alzheimer's disease (AD) is caused by a series of events initiated by the production and subsequent aggregation of the Alzheimer's amyloid b peptide (Ab), the so-called amyloid cascade hypothesis. Thus, a logical approach to treating AD is the development of small molecule inhibitors that either block the proteases that generate Ab from its precursor (b-and c-secretases) or interrupt and/or reverse Ab aggregation. To identify potent inhibitors of Ab aggregation, we have developed a high-throughput screen based on an earlier selection that effectively paired the folding quality control feature of the Escherichia coli Tat protein export system with aggregation of the 42-residue AD pathogenesis effecter Ab42. Specifically, a tripartite fusion between the Tat-dependent export signal ssTorA, the Ab42 peptide and the b-lactamase (Bla) reporter enzyme was found to be export incompetent due to aggregation of the Ab42 moiety. Here, we reasoned that small, cell-permeable molecules that inhibited Ab42 aggregation would render the ssTorA-Ab42-Bla chimera competent for Tat export to the periplasm where Bla is active against b-lactam antibiotics such as ampicillin. Using a fluorescence-based version of our assay, we screened a library of triazine derivatives and isolated four nontoxic, cellpermeable compounds that promoted efficient Tat-dependent export of ssTorA-Ab42-Bla. Each of these was subsequently shown to be a bona fide inhibitor of Ab42 aggregation using a standard thioflavin T fibrillization assay, thereby highlighting the utility of our bacterial assay as a useful screen for antiaggregation factors under physiological conditions.

show abstract

Inhibition and Modulation of γ-Secretase for Alzheimer's Disease

Cited by 130 publications

References 75 publications

Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design

Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design

Human CRB2 Inhibits γ-Secretase Cleavage of Amyloid Precursor Protein by Binding to the Presenilin Complex

Discovery of amyloid‐beta aggregation inhibitors using an engineered assay for intracellular protein folding and solubility

Contact Info

Product

Resources

About