PXD053165 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones |
Description | Nitrobenzothiazinones (BTZs) are undergoing late-stage development as a novel class of potent antituberculotic drug candidates with two compounds in clinical phases. BTZs inhibit decaprenylphosphoryl-β-D-ribose oxidase 1 (DprE1), a key enzyme in cell wall biosynthesis of mycobacteria. Their mechanism of action involves an in-situ reduction of the nitro moiety to a reactive nitroso intermediate capable of covalent binding to Cys387 in the catalytic cavity. The electron-deficient nature of the aromatic core is a key driver for the formation of hydride-Meisenheimer complexes (HMC) as main metabolites in vivo. To mimic the electrophilic character of the nitroso moiety, bioisosteric replacement against electrophilic warheads was attempted to reduce HMC formation without compromising covalent reactivity. Herein, we synthesized and characterized a set of various covalent warheads covering different reaction principles. Covalent inhibition was confirmed for all antimycobacterial compounds by enzymatic inhibition assays and protein mass spectrometry analysis. |
HostingRepository | PRIDE |
AnnounceDate | 2024-09-11 |
AnnouncementXML | Submission_2024-09-11_00:27:40.929.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Thomas Krüger |
SpeciesList | scientific name: Mycobacterium tuberculosis KT-0001; NCBI TaxID: 1400870; |
ModificationList | phosphorylated residue; acetylated residue; iodoacetamide derivatized residue |
Instrument | Orbitrap Exploris 480 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2024-06-17 00:46:22 | ID requested | |
⏵ 1 | 2024-09-11 00:27:41 | announced | |
Publication List
Keyword List
submitter keyword: LC-MS,Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones |
Contact List
Axel A. Brakhage |
contact affiliation | Department for Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute Jena - Leibniz-HKI, Jena Germany |
contact email | axel.brakhage@leibniz-hki.de |
lab head | |
Thomas Krüger |
contact affiliation | Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute |
contact email | thomas.krueger@leibniz-hki.de |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD053165
- Label: PRIDE project
- Name: Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones