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

Abstract

For the systematic perturbation of protein–protein interactions, we designed and synthesized tetra-substituted hexahydro-4H-pyrazino[2,1-c][1,2,4]triazine-4,7(6H)-diones as β-turn mimetics. 5c{3,9} stabilizes the direct interaction between LRS and RagD and activates mTORC1 in living cells.

Recent Advances in the Field of Amino Acid-Conjugated Aminoferrocenes—A Personal Perspective

“…Protein-protein interactions (PPIs) are critical for most biological processes [42,43], and are undertaken by mechanisms involving small "hot spots", hydrophobic structural regions containing from four to eight amino acids arranged as α-helices, β-sheets, or turns [44]. As disorders in PPIs can trigger diseases, the inhibitors capable of mimicing these recognition motifs at the PPI's interface [45,46], including peptidomimetic-based inhibitors, have been investigated for their drug-like properties [47,48]. Peptidomimetics are compounds whose essential pharmacophoric units mimic the structural elements of a natural peptide or protein to retain their ability to recognize and bind to a biological target, thereby achieving the desired biological effect [49].…”

Heterocycles as a Peptidomimetic Scaffold: Solid-Phase Synthesis Strategies

“…Kim et al developed a solid-phase synthesis methodology for the synthesis of β-turn mimetic-based leucyl-tRNA synthetase (LRS)-RagD PPI stabilizers. The solid-phase synthesis was performed on bromoacetal resin 38 ( Scheme 8 ) [ 36 ]. Various amines were loaded onto the resin via an S N 2 reaction, and then coupled with natural and unnatural Fmoc amino acids using O -(1 H -6-chlorobenzotriazole-1- yl )-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU)/DIPEA, followed by coupling with compound 41 .…”