154876-20-7Relevant academic research and scientific papers
Photo Cross-Linking Probes Containing ?-N-Thioacyllysine and ?-N-Acyl-(δ-aza)lysine Residues
B?k, Michael,Chakladar, Saswati,Laursen, Jonas S.,Madsen, Julie L. H.,Martín-Gago, Pablo,Olsen, Christian A.
supporting information, (2020/03/11)
Posttranslational modifications (PTMs) are important in the regulation of protein function, trafficking, localization, and marking for degradation. This work describes the development of peptide activity/affinity-based probes for the discovery of proteins that recognize novel acyl-based PTMs on lysine residues in the proteome. The probes contain surrogates of ?-N-acyllysine by introduction of either hydrazide or thioamide functionalities to circumvent hydrolysis of the modification during the experiments. In addition to the modified PTMs, the developed chemotypes were analyzed with respect to the effect of peptide sequence. The photo cross-linking conditions and subsequent functionalization of the covalent adducts were systematically optimized by applying fluorophore labeling and gel electrophoresis (in-gel fluorescence measurements). Finally, selected probes, containing the ?-N-glutaryllysine and ?-N-myristoyllysine analogues, were successfully applied for the enrichment of native, endogenous proteins from cell lysate, recapitulating the expected interactions of SIRT5 and SIRT2, respectively. Interestingly, the latter mentioned was able to pull down two different splice variants of SIRT2, which has not been achieved with a covalent probe before. Based on this elaborate proof-of-concept study, we expect that the technology will have broad future applications for pairing of novel PTMs with the proteins that target them in the cell.
Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure–Activity Relationship, Biostructural, and Kinetic Insight
Rajabi, Nima,Auth, Marina,Troelsen, Kathrin R.,Pannek, Martin,Bhatt, Dhaval P.,Fontenas, Martin,Hirschey, Matthew D.,Steegborn, Clemens,Madsen, Andreas S.,Olsen, Christian A.
supporting information, p. 14836 - 14841 (2017/11/10)
The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more “drug-like” properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology.
ANTIVIRAL PROTEASE INHIBITORS
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Page/Page column 491, (2008/06/13)
The invention is related to compounds of Formula I or a pharmaceutically acceptable salt, solvate, ester, and /or phosphonate thereof, compositions containing such compounds, and therapeutic methods that include the administration of such compounds.
HIV PROTEASE INHIBITING COMPOUNDS
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Page/Page column 115-116, (2010/02/12)
A compound of the formula (I) is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
HIV PROTEASE INHIBITING COMPOUNDS
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Page/Page column 59, (2010/02/12)
A compound of the formula is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
