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For the systematic perturbation of protein-protein interactions, we designed and synthesized tetra-substituted hexahydro-4 H -pyrazino[2,1- c ][1,2,4]triazine-4,7(6 H )-diones as β-turn mimetics. We then devised a new synthetic route to obtain β-turn mimetic scaffolds via tandem N -acyliminium cyclization and constructed a 162-member library of tetra-substituted pyrazinotriazinediones with an average purity of 90% using a solid-phase parallel synthesis platform. Each library member was subjected to ELISA-based modulator screening for the LRS-RagD interaction, which plays a pivotal role in the nutrient-dependent mTORC1 signalling pathway. Western blot analysis of phosphorylated S6K1 as well as FRET-based imaging confirmed that 5c{3,9} stabilizes the direct interaction between LRS and RagD and activates mTORC1 in live cells under leucine-deprived conditions. Thus, 5c{3,9} can be used as a new research tool for studying the non-canonical role of LRS.

β-Turn mimetic-based stabilizers of protein–protein interactions for the study of the non-canonical roles of leucyl-tRNA synthetase