AI Article Synopsis
- Traditional medicines can lead to the discovery of useful drug compounds, but figuring out how they work in the body can be difficult.
- Researchers identified a compound called (Z)-(+)-isochaihulactone (1) that effectively inhibits drug-resistant cancer cells and tumors in mice.
- They found that this compound works by irreversibly targeting a specific protein (GAPDH), which helps trigger cell death in a novel way, offering a potential new strategy for treating resistant cancers.
Article Abstract
Traditional medicines provide a fertile ground to explore potent lead compounds, yet their transformation into modern drugs is fraught with challenges in deciphering the target that is mechanistically valid for its biological activity. Herein we reveal that (Z)-(+)-isochaihulactone (1) exhibited significant inhibition against multiple-drug-resistant (MDR) cancer cell lines and mice xenografts. NMR spectroscopy showed that 1 resisted an off-target thiolate, thus indicating that 1 was a target covalent inhibitor (TCI). By identifying the pharmacophore of 1 (α,β-unsaturated moiety), a probe derived from 1 was designed and synthesized for TCI-oriented activity-based proteome profiling. By MS/MS and computer-guided molecular biology approaches, an affinity-driven Michael addition of the noncatalytic C247 residue of GAPDH was found to control the "ON/OFF" switch of apoptosis through non-canonically nuclear GAPDH translocation, which bypasses the common apoptosis-resistant route of MDR cancers.
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| http://dx.doi.org/10.1002/anie.201801618 | DOI Listing |
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Article Synopsis
- Traditional medicines can lead to the discovery of useful drug compounds, but figuring out how they work in the body can be difficult.
- Researchers identified a compound called (Z)-(+)-isochaihulactone (1) that effectively inhibits drug-resistant cancer cells and tumors in mice.
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PLoS One
May 2016
Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
To extend and improve the utility of the streptavidin-binding peptide tag (SBP-tag) in applications ranging from affinity purification to the reversible immobilization of recombinant proteins, a cysteine residue was introduced to the streptavidin mutein SAVSBPM18 and the SBP-tag to generate SAVSBPM32 and SBP(A18C), respectively. This pair of derivatives is capable of forming a disulfide bond through the newly introduced cysteine residues. SAVSBPM32 binds SBP-tag and biotin with binding affinities (Kd ~ 10-8M) that are similar to SAVSBPM18.
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