A number of naphthofuranones were synthesized and tested for COX-1 and COX-2 inhibition. Few of them were identified as selective COX-2 inhibitors. Structure-activity relationship studies within the series are discussed.
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Mature chromatin packing domains persist after RAD21 depletion in 3D.
Sci Adv
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Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA.
Understanding chromatin organization requires integrating measurements of genome connectivity and physical structure. It is well established that cohesin is essential for TAD and loop connectivity features in Hi-C, but the corresponding change in physical structure has not been studied using electron microscopy. Pairing chromatin scanning transmission electron tomography with multiomic analysis and single-molecule localization microscopy, we study the role of cohesin in regulating the conformationally defined chromatin nanoscopic packing domains.
View Article and Find Full Text PDFConformationally Restricted Grp94-Selective Inhibitors.
ACS Omega
January 2025
Department of Chemistry and Biochemistry, Warren Center for Drug Discovery, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, Indiana 46556, United States.
Selective inhibition of glucose regulated protein 94 (Grp94), the most structurally unique isoform of heat shock protein 90 (Hsp90), has been implicated in the treatment of various disease states, including primary open-angle glaucoma and metastatic cancer. In this study, nine analogues were designed and synthesized by conformationally restricting , a second generation Grp94-selective inhibitor. Conformational constraints were applied to restrict the rotatable bonds and to bias the benzyl moiety into the Grp94 site 1 pocket as well as to reduce the entropic penalty paid upon binding.
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Proteins
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Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, India.
Short-length peptides are used as therapeutics due to their high target specificity and low toxicity; for example, peptides are designed for targeting the interaction between oncogenic protein p53 and E3 ubiquitin ligase MDM2. These peptide therapeutics form a class of successful inhibitors. To design such peptide-based inhibitors, stapling is one of the methods in which amino acid side chains are stitched together to get conformationally rigid peptides, ensuring effective binding to their partners.
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January 2025
Department Chemistry and Biochemistry, Clemens-Schöpf-Institute, Technical University Darmstadt Peter-Grünberg Strasse 4, 64287, Darmstadt, Germany.
Article Synopsis
- Macrocycles are seen as effective tools for targeting hard-to-reach proteins inside cells, but improving them from initial linear structures is still a work in progress.
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Sequence and structural determinants of RNAPII CTD phase-separation and phosphorylation by CDK7.
Nat Commun
October 2024
CEITEC - Central European Institute of Technology, Masaryk University, Brno, Czechia.
The intrinsically disordered carboxy-terminal domain (CTD) of the largest subunit of RNA Polymerase II (RNAPII) consists of multiple tandem repeats of the consensus heptapeptide Y1-S2-P3-T4-S5-P6-S7. The CTD promotes liquid-liquid phase-separation (LLPS) of RNAPII in vivo. However, understanding the role of the conserved heptad residues in LLPS is hampered by the lack of direct biochemical characterization of the CTD.
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