Abstract
Human sirtuin 5 (SIRT5) plays pivotal roles in metabolic pathways and other biological processes, and is involved in several human diseases including cancer. Development of new potent and selective SIRT5 inhibitors is currently desirable to provide potential therapeutics for related diseases. Herein, we report a series of new 3-thioureidopropanoic acid derivatives, which were designed to mimic the binding features of SIRT5 glutaryl-lysine substrates. Structure-activity relationship studies revealed several compounds with low micromolar inhibitory activities to SIRT5. Computational and biochemical studies indicated that these compounds exhibited competitive SIRT5 inhibition with respect to the glutaryl-lysine substrate rather than nicotinamide adenine dinucleotide cofactor. Moreover, they showed high selectivity for SIRT5 over SIRT1-3 and 6 and could stabilize SIRT5 proteins as revealed by thermal shift analyses. This work provides an effective substrate-mimicking strategy for future inhibitor design, and offers new inhibitors to investigate their therapeutic potentials in SIRT5-associated disease models.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
