Taming PRMT5-adaptor protein interactions

Abstract

Protein arginine methyltransferase (PRMT)-5 is a prominent epigenetic regulator and therapeutic target. Recently, Krzyzanowski et al. identified stapled peptides that inhibit the interaction of PRMT5 with two of its adaptor proteins. This discovery creates opportunities for novel therapeutic development by selectively modulating PRMT5 activity.

Keywords: Rio domain-containing protein (RioK1); chloride channel nucleotide sensitive protein 1A (pICln); protein arginine methyltransferase 5 (PRMT5); protein-protein interaction (PPI) inhibitor; solid-phase peptide synthesis (SPPS); stapled peptide.

Figure 1.

Structural evolution of macrocyclic peptides for inhibiting PRMT5–adaptor protein interactions. (A) Using the co-crystal of RioK1-derived peptide (top peptide) in complex with PRMT5 and computational modeling, a peptide stapling strategy was proposed (bottom peptide). It was speculated that replacing Gly14 with a (D)-residue (a-shown in blue), Asp17 with a (D) or (L)-residue (b-shown in blue), and that tethering these residues with a 4 or 5 atom linker (shown in pink) would be optimal. (B) The first generation of stapled peptides were generated through ring closing metathesis (RCM), and macrolactamization (these macrocyclization reactions were performed on-resin). Representative variations in the peptides include: different linker lengths of the chains adjacent to the olefin and amide generated from ring closing (m and n shown in pink), both (D) and (L) configurations of the modified residue replacing Asp17 (b- shown in blue), and reduction of the olefin (generated from RCM) to the alkane. (C) Further optimization led to compound 1 with a K_i value of 313 nM. The peptide has a saturated (generated from reduction of the olefin) 5-atom linker (shown in pink), and an (L) configuration of the modified residue replacing Asp17 (b- shown in blue). (D) Optimization of the residues in a simplified linear peptide (not shown) followed by incorporation into compound 1 (shown in green) led to stapled peptide 2 with a K_i value of 66 nM.