ArticleACS pharmacology & translational science2022
Structure-Based Design and Biological Evaluation of Novel Caspase-2 Inhibitors Based on the Peptide AcVDVAD-CHO and the Caspase-2-Mediated Tau Cleavage Sequence YKPVD314.
Article in ACS pharmacology & translational science, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The trial behind it
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Multi-target-directed therapeutic strategies for Alzheimer's disease: controlling amyloid-β aggregation, metal ion homeostasis, and enzyme inhibition.Chemical science · 2025Review
- Caspases in Alzheimer's Disease: Mechanism of Activation, Role, and Potential Treatment.Molecular neurobiology · 2024Review
- Post-Translational Modifications in Tau and Their Roles in Alzheimer's Pathology.Current Alzheimer research · 2024Review
- An electrophilic fragment screening for the development of small molecules targeting caspase-2.European journal of medicinal chemistry · 2023Article
- Apoptotic cell death in disease-Current understanding of the NCCD 2023.Cell death and differentiation · 2023Review
- Targeting caspase-2 interactions with tau in Alzheimer's disease and related dementias.Translational research : the journal of laboratory and clinical medicine · 2023Review
- Characterization of caspase-2 inhibitors based on specific sites of caspase-2-mediated proteolysis.Archiv der Pharmazie · 2022Article
- Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy.ACS chemical neuroscience · 2022Article
Corrections and comments
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Authors and funding
15 authors at 2 institutions in 2 countries.
Funding
Abstract
Alzheimer's disease (AD) was first described by Alois Alzheimer over 100 years ago, but there is still no overarching theory that can explain its cause in detail. There are also no effective therapies to treat either the cause or the associated symptoms of this devastating disease. A potential approach to better understand the pathogenesis of AD could be the development of selective caspase-2 (Casp2) probes, as we have shown that a Casp2-mediated cleavage product of tau (Δtau314) reversibly impairs cognitive and synaptic function in animal models of tauopathies. In this article, we map out the Casp2 binding site through the preparation and assay of a series of 35 pentapeptide inhibitors with the goal of gaining selectivity against caspase-3 (Casp3). We also employed computational docking methods to understand the key interactions in the binding pocket of Casp2 and the differences predicted for binding at Casp3. Moreover, we crystallographically characterized the binding of selected pentapeptides with Casp3. Furthermore, we engineered and expressed a series of recombinant tau mutants and investigated them in an in vitro cleavage assay. These studies resulted in simple peptidic inhibitors with nanomolar affinity, for example, AcVDV(Dab)D-CHO (
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.