InhA, the enoyl-ACP reductase in Mycobacterium tuberculosis is an attractive target for the development of novel drugs against tuberculosis, a disease that kills more than two million people each year. InhA is the target of the current first line drug isoniazid for the treatment of tuberculosis infections. Compounds that directly target InhA and do not require activation by the mycobacterial catalase-peroxidase KatG are promising candidates for treating infections caused by isoniazid-resistant strains. Previously we reported the synthesis of several diphenyl ethers with nanomolar affinity for InhA. However, these compounds are rapid reversible inhibitors of the enzyme, and based on the knowledge that long drug target residence times are an important factor for in vivo drug activity, we set out to generate a slow onset inhibitor of InhA using structure-based drug design. 2-(o-Tolyloxy)-5-hexylphenol (PT70) is a slow, tight binding inhibitor of InhA with a K 1 value of 22 pM. PT70 binds preferentially to the InhA⅐NAD ؉ complex and has a residence time of 24 min on the target, which is 14,000 times longer than that of the rapid reversible inhibitor from which it is derived. The 1.8 Å crystal structure of the ternary complex between InhA, NAD ؉ , and PT70 reveals the molecular details of enzymeinhibitor recognition and supports the hypothesis that slow onset inhibition is coupled to ordering of an active site loop, which leads to the closure of the substrate-binding pocket.
Bioorthogonal
reactions, including the strain-promoted azide–alkyne
cycloaddition (SPAAC) and inverse electron demand Diels–Alder
(iEDDA) reactions, have become increasingly popular for live-cell
imaging applications. However, the stability and reactivity of reagents
has never been systematically explored in the context of a living
cell. Here we report a universal, organelle-targetable system based
on HaloTag protein technology for directly comparing bioorthogonal
reagent reactivity, specificity, and stability using clickable HaloTag
ligands in various subcellular compartments. This system enabled a
detailed comparison of the bioorthogonal reactions in live cells and
informed the selection of optimal reagents and conditions for live-cell
imaging studies. We found that the reaction of sTCO with monosubstituted
tetrazines is the fastest reaction in cells; however, both reagents
have stability issues. To address this, we introduced a new variant
of sTCO, Ag-sTCO, which has much improved stability and can be used
directly in cells for rapid bioorthogonal reactions with tetrazines.
Utilization of Ag complexes of conformationally strained trans-cyclooctenes should greatly expand their usefulness especially when
paired with less reactive, more stable tetrazines.
Background: Potent GSMs have been identified that lower A42; however, the mechanism of modulation is not well understood.
Results:The photoaffinity probe E2012-BPyne specifically labels PS1-NTF at a unique site. Conclusion: Acid and imidazole GSMs bind to distinct sites on PS1-NTF and are differentially affected by L458. Significance: Our results provide evidence for multiple binding sites within ␥-secretase that confer specific modulatory effects.
Molecular
editing such as insertion, deletion, and single atom
exchange in highly functionalized compounds is an aspirational goal
for all chemists. Here, we disclose a photoredox protocol for the
replacement of a single fluorine atom with hydrogen in electron-deficient
trifluoromethylarenes including complex drug molecules. A robustness
screening experiment shows that this reductive defluorination tolerates
a range of functional groups and heterocycles commonly found in bioactive
molecules. Preliminary studies allude to a catalytic cycle whereby
the excited state of the organophotocatalyst is reductively quenched
by the hydrogen atom donor, and returned in its original oxidation
state by the trifluoromethylarene.
The design, synthesis, and application of [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis of sulfur(VI) fluorides, is described. The utility of AISF is demonstrated in the synthesis of a diverse array of aryl fluorosulfates and sulfamoyl fluorides under mild conditions. Additionally, a single-step preparation of AISF was developed that installed the bis(fluorosulfonyl)imide group on acetanilide utilizing an oxidative C-H functionalization protocol.
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