Ralph Mazitschek
@mazit
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ChemicalBiologists, all things small molecule at the corner of science and nature
Boston, MA
Joined March 2009
In the recent issue of @nchembio we report the development of #CoraFluors, a #novel class of bright and stable TR-FRET donors optimized for biological #application, including measuring the binding of drug molecules to their targets, directly in #livecells and in real time 🧪(1/n).
The cover of our November issue ( features a class of luminescent terbium-based probes called CoraFluors ( used for detecting ligand-bound protein targets by TR-FRET.
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RT @CellChemBiol: Voices: @antolin_aa, Yimon Aye, @LironBarPeled, @Elena_De_Vita, @nata_dudkina, @MichaelCJewett, @hannahjanekc, @mazit, an….
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RT @vicmarando: Excited to see this out! Congrats to @HammelForrest and the whole team!! @Chemist_Payne @mazit @HarvardMicro .Identificati….
pubs.acs.org
O-GlcNAc transferase (OGT) is an essential mammalian enzyme that binds thousands of different proteins, including substrates that it glycosylates and nonsubstrate interactors that regulate its...
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RT @brian_b_liau: Excited to share 2 preprints, together showing how mechanisms of a molecular glue & E3 ligase cancer mutations serendipit….
biorxiv.org
Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function[1][1]. As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently...
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Rockstar work championed by @Chemist_Payne and Saki Ichikawa synergistically combines #CoraFluors and #Cyclimids into a powerful platform approach to accelerate degrader development and comprehensive characterization.
Our newest work in collaboration with Saki Ichikawa and @drcmwoo @mazit is now online @CellChemBiol! Here is a free-to-read link:.
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Awesome collaboration with #BullockLab and @Chemist_Payne! Combining our complementary expertise, we shed new light on the CUL-3-KEAP1 complex, establish a straightforward assay to measure CUL3 binding to its adaptor proteins, and reveal CDDO’s activity as a “partial antagonist”.
The Bullock lab @CMDOxford has a new paper on KEAP1-CUL3 structure, TR-FRET and inhibition by CDDO. Great collaboration with Ralph Mazitschek @mazit DOI:
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I wonder if we will see certain footage played in reverse to suggest some “visitors” just came to fix things that were broken.
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RT @DSzymborski: My Saturday fun project: using AI, every US president as a Pixar character.
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RT @Chemist_Payne: Preprint out! . KEAP1-CUL3 structure, an awesome new assay platform for BTB domain-containing proteins, and elucidating….
biorxiv.org
KEAP1 promotes the ubiquitin-dependent degradation of NRF2 by assembling into a CUL3-dependent ubiquitin ligase complex. Oxidative and electrophilic stress inhibit KEAP1 allowing NRF2 to accumulate...
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RT @NatureComms: Authors @mazit @Mark_A_Tye @Chemist_Payne @dyann_wirth @LabOppermann @MGHCSB @HarvardChanSPH @broadinstitute @UniofOxford….
nature.com
Nature Communications - The development of antimalarials against the human liver and asexual blood stages is one of the top public health challenges. Here, the authors report a single-step...
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P.S. Like many folks on #ScienceTwitter, we have also encountered hostile🗡️ referees during the review process of this manuscript. I am grateful🙏 to the editor for recognizing this and not taking the easy way out but recruiting additional referees. 12/.
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Also thanks to our institutions and funding support @MGHCSB, @MGH_RI, @broadinstitute, @HarvardChanSPH, @broadinstitute, @UniofOxford, @HarvardCCB, @chemical_phd, @NIAIDFunding, @NSF, @scienceinboston 11/.
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Nothing of this would have been possible without the awesome students and collaborators, @Mark_A_Tye, @Chemist_Payne, @kritika_singh24, @MariaMMota2, @ElizabethWinze1, @DerbyLabDuke, @dyann_wirth, @LabOppermann. 10/.
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Guided by our structural data we have furthermore been able to develop the first genuine aaRS triple-site inhibitors, as illustrated by MAT436 (PDB: 7QC1), that simultaneously target all three substrate pockets. 9/
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Our lead compound, NCP26, is active against liver and asexual blood🩸stage Plasmodium parasites and displays good cellular selectivity. Which, interestingly, is in part the consequence of the higher substrate affinity of host vs. parasite ProRS. 8/
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Supported by this platform, we have optimized a series of proline uncompetitive ligands that do not exhibit cross-resistance with halofuginone and exhibit a very low propensity for resistance evolution. 7/.
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Using our new #CoraFluor TR-FRET ⚡️technology, we have developed a robust (Z’ > 0.9) mix-and-read🍸 ligand displacement assay for Plasmodium and human ProRS that is > 1000-fold more sensitive than current assays and enables facile determination of the mode of inhibition. 6/
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However, despite their potential as drug targets, the lack of sensitive, versatile, and robust assay platforms for ProRS and other aminoacyl-tRNA synthetases (aaRS) has broadly impeded aaRS drug development efforts in general. 5/
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Unfortunately, the poor tolerability of halofuginone analogs and the ability of malaria parasites to develop rapid halofuginone resistance by modulation of proline homeostasis, has dampened enthusiasm 🫤 for this inhibitor chemotype. 4/.
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Halofuginone is one of the most potent antimalarials discovered to date. It is an analog of febrifugine, the active ingredient of a #TraditionalChineseMedicine herbal 🌿remedy, which has been used for millennia to treat fevers🤒and malaria. 3/
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