FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2411502634> ?p ?o ?g. }

• W2411502634 endingPage "2724" @default.
• W2411502634 startingPage "2716" @default.
• W2411502634 abstract "Many therapeutically important enzymes are present in multiple cellular compartments, where they can carry out markedly different functions; thus, there is a need for pharmacological strategies to selectively manipulate distinct pools of target enzymes. Insulin-degrading enzyme (IDE) is a thiol-sensitive zinc-metallopeptidase that hydrolyzes diverse peptide substrates in both the cytosol and the extracellular space, but current genetic and pharmacological approaches are incapable of selectively inhibiting the protease in specific subcellular compartments. Here, we describe the discovery, characterization, and kinetics-based optimization of potent benzoisothiazolone-based inhibitors that, by virtue of a unique quasi-irreversible mode of inhibition, exclusively inhibit extracellular IDE. The mechanism of inhibition involves nucleophilic attack by a specific active-site thiol of the enzyme on the inhibitors, which bear an isothiazolone ring that undergoes irreversible ring opening with the formation of a disulfide bond. Notably, binding of the inhibitors is reversible under reducing conditions, thus restricting inhibition to IDE present in the extracellular space. The identified inhibitors are highly potent (IC50(app) = 63 nM), nontoxic at concentrations up to 100 μM, and appear to preferentially target a specific cysteine residue within IDE. These novel inhibitors represent powerful new tools for clarifying the physiological and pathophysiological roles of this poorly understood protease, and their unusual mechanism of action should be applicable to other therapeutic targets." @default.
• W2411502634 created "2016-06-24" @default.
• W2411502634 creator A5005325846 @default.
• W2411502634 creator A5007920767 @default.
• W2411502634 creator A5013636406 @default.
• W2411502634 creator A5035213231 @default.
• W2411502634 creator A5041449809 @default.
• W2411502634 creator A5043898760 @default.
• W2411502634 creator A5045256278 @default.
• W2411502634 creator A5051344955 @default.
• W2411502634 creator A5052499072 @default.
• W2411502634 creator A5053933190 @default.
• W2411502634 creator A5055376230 @default.
• W2411502634 creator A5062137111 @default.
• W2411502634 creator A5065641764 @default.
• W2411502634 creator A5084918547 @default.
• W2411502634 creator A5085206283 @default.
• W2411502634 creator A5085356292 @default.
• W2411502634 creator A5090366405 @default.
• W2411502634 date "2015-09-30" @default.
• W2411502634 modified "2023-10-15" @default.
• W2411502634 title "Selective Targeting of Extracellular Insulin-Degrading Enzyme by Quasi-Irreversible Thiol-Modifying Inhibitors" @default.
• W2411502634 cites W1596950278 @default.
• W2411502634 cites W1971729688 @default.
• W2411502634 cites W1973716848 @default.
• W2411502634 cites W1982842980 @default.
• W2411502634 cites W1983839663 @default.
• W2411502634 cites W1991001144 @default.
• W2411502634 cites W1993751382 @default.
• W2411502634 cites W2001555590 @default.
• W2411502634 cites W2003872355 @default.
• W2411502634 cites W2004186568 @default.
• W2411502634 cites W2008430447 @default.
• W2411502634 cites W2014306255 @default.
• W2411502634 cites W2021624791 @default.
• W2411502634 cites W2023251219 @default.
• W2411502634 cites W2032694200 @default.
• W2411502634 cites W2034337315 @default.
• W2411502634 cites W2035393691 @default.
• W2411502634 cites W2036291177 @default.
• W2411502634 cites W2041015024 @default.
• W2411502634 cites W2041189078 @default.
• W2411502634 cites W2048361834 @default.
• W2411502634 cites W2050302468 @default.
• W2411502634 cites W2052907531 @default.
• W2411502634 cites W2053684471 @default.
• W2411502634 cites W2068402943 @default.
• W2411502634 cites W2098546374 @default.
• W2411502634 cites W2100531384 @default.
• W2411502634 cites W2102377211 @default.
• W2411502634 cites W2105649494 @default.
• W2411502634 cites W2108850637 @default.
• W2411502634 cites W2111067301 @default.
• W2411502634 cites W2120836040 @default.
• W2411502634 cites W2131124255 @default.
• W2411502634 cites W2135732933 @default.
• W2411502634 cites W2138997437 @default.
• W2411502634 cites W2141087520 @default.
• W2411502634 cites W2145124786 @default.
• W2411502634 cites W3022771863 @default.
• W2411502634 doi "https://doi.org/10.1021/acschembio.5b00334" @default.
• W2411502634 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26398879" @default.
• W2411502634 hasPublicationYear "2015" @default.
• W2411502634 type Work @default.
• W2411502634 sameAs 2411502634 @default.
• W2411502634 citedByCount "21" @default.
• W2411502634 countsByYear W24115026342016 @default.
• W2411502634 countsByYear W24115026342018 @default.
• W2411502634 countsByYear W24115026342019 @default.
• W2411502634 countsByYear W24115026342020 @default.
• W2411502634 countsByYear W24115026342021 @default.
• W2411502634 countsByYear W24115026342022 @default.
• W2411502634 crossrefType "journal-article" @default.
• W2411502634 hasAuthorship W2411502634A5005325846 @default.
• W2411502634 hasAuthorship W2411502634A5007920767 @default.
• W2411502634 hasAuthorship W2411502634A5013636406 @default.
• W2411502634 hasAuthorship W2411502634A5035213231 @default.
• W2411502634 hasAuthorship W2411502634A5041449809 @default.
• W2411502634 hasAuthorship W2411502634A5043898760 @default.
• W2411502634 hasAuthorship W2411502634A5045256278 @default.
• W2411502634 hasAuthorship W2411502634A5051344955 @default.
• W2411502634 hasAuthorship W2411502634A5052499072 @default.
• W2411502634 hasAuthorship W2411502634A5053933190 @default.
• W2411502634 hasAuthorship W2411502634A5055376230 @default.
• W2411502634 hasAuthorship W2411502634A5062137111 @default.
• W2411502634 hasAuthorship W2411502634A5065641764 @default.
• W2411502634 hasAuthorship W2411502634A5084918547 @default.
• W2411502634 hasAuthorship W2411502634A5085206283 @default.
• W2411502634 hasAuthorship W2411502634A5085356292 @default.
• W2411502634 hasAuthorship W2411502634A5090366405 @default.
• W2411502634 hasBestOaLocation W24115026342 @default.
• W2411502634 hasConcept C161624437 @default.
• W2411502634 hasConcept C181199279 @default.
• W2411502634 hasConcept C182220744 @default.
• W2411502634 hasConcept C185592680 @default.
• W2411502634 hasConcept C2776714187 @default.
• W2411502634 hasConcept C2779201268 @default.
• W2411502634 hasConcept C2780331951 @default.

• next