ArticleJournal of medicinal chemistry2015
X-ray crystal structures of Escherichia coli RNA polymerase with switch region binding inhibitors enable rational design of squaramides with an improved fraction unbound to human plasma protein.
Article in Journal of medicinal chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 41 citations in OpenAlex.
- Phytochemical profiling, metabolomics, and molecular docking studies of Atriplex halimus aerial parts revealing potential insecticidal activity against the malaria vector Anopheles pharoensis.Scientific reports · 2026Article
- Targeting Bacterial RNA Polymerase: Harnessing Simulations and Machine Learning to Design Inhibitors for Drug-Resistant Pathogens.Biochemistry · 2025Review
- Reaction contest: hydrolysisRSC advances · 2024Article
- Pseudouridimycin-A Potent Nucleoside Inhibitor of the RNA Polymerase Beta Prime Subunit ofACS omega · 2023Article
- Silver-Free Gold-Catalyzed Heterocyclizations through Intermolecular H-Bonding Activation.The Journal of organic chemistry · 2023Article
- How to Shut Down Transcription in Archaea during Virus Infection.Microorganisms · 2022Review
- Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations.International journal of molecular sciences · 2022Article
- Role of bacterial RNA polymerase gate opening dynamics in DNA loading and antibiotics inhibition elucidated by quasi-Markov State Model.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Evaluation of Bacterial RNA Polymerase Inhibitors in aACS infectious diseases · 2020Article
- Synthesis of Novel 2-(Het)arylpyrrolidine Derivatives and Evaluation of Their Anticancer and Anti-Biofilm Activity.Molecules (Basel, Switzerland) · 2019Article
- [New inhibitors targeting bacterial RNA polymerase].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2019Review
- Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis.Molecular cell · 2018Article
- Structure-function comparisons of (p)ppApp vs (p)ppGpp for Escherichia coli RNA polymerase binding sites and for rrnB P1 promoter regulatory responses in vitro.Biochimica et biophysica acta. Gene regulatory mechanisms · 2018Article
- Review
- Cryo-EM structure ofThe Journal of biological chemistry · 2018Article
- Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3).Molecular cell · 2018Article
- Allosteric Effector ppGpp Potentiates the Inhibition of Transcript Initiation by DksA.Molecular cell · 2018Article
- Dynamics of GreB-RNA polymerase interaction allow a proofreading accessory protein to patrol for transcription complexes needing rescue.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Bacterial Transcription as a Target for Antibacterial Drug Development.Microbiology and molecular biology reviews : MMBR · 2016Review
- Bacterial RNA Polymerase-DNA Interaction-The Driving Force of Gene Expression and the Target for Drug Action.Frontiers in molecular biosciences · 2016Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Squaramides constitute a novel class of RNA polymerase inhibitors of which genetic evidence and computational modeling previously have suggested an inhibitory mechanism mediated by binding to the RNA polymerase switch region. An iterative chemistry program increased the fraction unbound to human plasma protein from below minimum detection levels, i.e., <1% to 4-6%, while retaining biochemical potency. Since in vitro antimicrobial activity against an efflux-negative strain of Haemophilus influenzae was 4- to 8-fold higher, the combined improvement was at least 20- to 60-fold. Cocrystal structures of Escherichia coli RNA polymerase with two key squaramides showed displacement of the switch 2, predicted to interfere with the conformational change of the clamp domain and/or with binding of template DNA, a mechanism akin to that of natural product myxopyronin. Furthermore, the structures confirmed the chemical features required for biochemical potency. The terminal isoxazole and benzyl rings bind into distinct relatively narrow, hydrophobic pockets, and both are required for biochemical potency. In contrast, the linker composed of squarate and piperidine accesses different conformations in their respective cocrystal structures with RNA polymerase, reflecting its main role of proper orientation of the aforementioned terminal rings. These observations further explain the tolerance of hydrophilic substitutions in the linker region that was exploited to improve the fraction unbound to human plasma protein while retaining biochemical potency.
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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.