ArticleBiochemistry2022
Molecular Features of CA-074 pH-Dependent Inhibition of Cathepsin B.
Article in Biochemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 40 citations in OpenAlex.
- The role of lysosome-dependent cell death in cancer.Apoptosis : an international journal on programmed cell death · 2026Review
- Gaining Insights Into the Formation of the Cathepsin B Inhibitor II-Human Serum Albumin Complex: A Multidisciplinary Approach.Luminescence : the journal of biological and chemical luminescence · 2026Article
- Macrophage-derived cathepsin B disrupts intestinal tight junctions through occludin degradation and promotes alcohol-associated liver disease.Journal of hepatology · 2026Article
- Development of Cathepsin B‑Activatable Cell-Penetrating Peptides for Tumor Targeting.ACS pharmacology & translational science · 2026Article
- Macrophage reprogramming through scavenger receptor-guided and cathepsin B-triggered nanodelivery: from intracellular mechanisms to translational applications.Frontiers in immunology · 2026Review
- Computer-aided Drug Design for Alzheimer's Disease: Recent Advancements and Future Perspectives.Current topics in medicinal chemistry · 2026Review
- Enzymatic combinatorial synthesis of E-64 and related cysteine protease inhibitors.Nature chemical biology · 2025Article
- Lysosome-dependent cell death: disease implications and potential therapeutic targets.Molecular biology reports · 2025Review
- Neutral pH-Selective Inhibition of Cytosolic Cathepsin B: A Novel Drug Targeting Strategy for Traumatic Brain Injury and Alzheimer's Disease.ACS chemical biology · 2025Review
- Cathepsin B Levels Correlate with the Severity of Canine Myositis.Biomolecules · 2025Article
- Identification of novel potential cathepsin-B inhibitors through pharmacophore-based virtual screening, molecular docking, and dynamics simulation studies for the treatment of Alzheimer's disease.Molecular diversity · 2024Article
- The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.Molecular neurodegeneration · 2024Article
- Cathepsin B- and L-like Protease Activities Are Induced During Developmental Barley Leaf Senescence.Plants (Basel, Switzerland) · 2024Article
- Ruthenium-Cathepsin Inhibitor Conjugates for Green Light-Activated Photodynamic Therapy and Photochemotherapy.Inorganic chemistry · 2024Article
- The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.Research square · 2024Article
- The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.bioRxiv : the preprint server for biology · 2023Article
- Distinct Cleavage Properties of Cathepsin B Compared to Cysteine Cathepsins Enable the Design and Validation of a Specific Substrate for Cathepsin B over a Broad pH Range.Biochemistry · 2023Article
- Isolation of Nocuolin A and Synthesis of New Oxadiazine Derivatives. Design, Synthesis, Molecular Docking, Apoptotic Evaluation, and Cathepsin B Inhibition.Marine drugs · 2023Article
- Enzyme-Responsive Double-Locked Photodynamic Molecular Beacon for Targeted Photodynamic Anticancer Therapy.Journal of the American Chemical Society · 2023Article
- Dipeptide-Derived Alkynes as Potent and Selective Irreversible Inhibitors of Cysteine Cathepsins.Journal of medicinal chemistry · 2023Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
CA-074 is a selective inhibitor of cathepsin B, a lysosomal cysteine protease. CA-074 has been utilized in numerous studies to demonstrate the role of this protease in cellular and physiological functions. Cathepsin B in numerous human disease mechanisms involves its translocation from acidic lysosomes of pH 4.6 to neutral pH 7.2 of cellular locations, including the cytosol and extracellular environment. To gain in-depth knowledge of CA-074 inhibition under these different pH conditions, this study evaluated the molecular features, potency, and selectivity of CA-074 for cathepsin B inhibition under acidic and neutral pH conditions. This study demonstrated that CA-074 is most effective at inhibiting cathepsin B at an acidic pH of 4.6 with nM potency, which was more than 100-fold more potent than its inhibition at a neutral pH of 7.2. The pH-dependent inhibition of CA-074 was abolished by methylation of its C-terminal proline, indicating the requirement for the free C-terminal carboxyl group for pH-dependent inhibition. Under these acidic and neutral pH conditions, CA-074 maintained its specificity for cathepsin B over other cysteine cathepsins, displayed irreversible inhibition, and inhibited diverse cleavages of peptide substrates of cathepsin B assessed by profiling mass spectrometry. Molecular docking suggested that pH-dependent ionic interactions of the C-terminal carboxylate of CA-074 occur with His110 and His111 residues in the S2' subsite of the enzyme at pH 4.6, but these interactions differ at pH 7.2. While high levels of CA-074 or CA-074Me (converted by cellular esterases to CA-074) are used in biological studies to inhibit cathepsin B at both acidic and neutral pH locations, it is possible that adjusted levels of CA-074 or CA-074Me may be explored to differentially affect cathepsin B activity at these different pH values. Overall, the results of this study demonstrate the molecular, kinetic, and protease specificity features of CA-074 pH-dependent inhibition of cathepsin B.
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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.