Scheme 1.

Synthesis of LCL-stPERML-R7. A conventional Fmoc-based solid-phase method was performed to synthesize the designated peptides. After construction of the PERML-R7 moiety, stapling was carried out on resin using the ring-closing metathesis reaction and the relevant E3 ligase ligand was conjugated to the ε-amino group of the N-terminal Lys residue via an ethylene glycol-based linker. All six peptides PERML, PERML-R7, stPERML, stPERML-R7, LCL-PERML-R7 and LCL-stPERML-R7 were cleaved from resin using a trifluoroacetic acid (TFA) cocktail and purified by reversed-phase high-performance liquid chromatography. Abbreviation: Boc; tert-butoxycarbonyl, Pbf; 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl, Trt; Trityl, RCM; ring-closing metathesis.