Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryl-lysine substrates

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. [Display omitted] •Designing new SIRT5 inhibitors by mimicking glutaryl-lysine substrates.•Synthesis of 47 new 3-thioureidopropanoic acid derivatives as SIRT5 inhibitors.•Competitive SIRT5 inhibition to glutaryl-lysine substrate rather than NAD+.•New inhibitors can stabilize SIRT5 proteins.