Synthesis of new modified truncated peptides and inhibition of glycogen phosphorylase

Abstract

The first solution state structural analysis (NMR) of the C-terminal sequence of human G(L) that binds to glycogen phosphorylase a (GPa), PEWPSYLGYEKLGPYY-NH(2) (1), showed it to be in a random coil conformation. This was supported by molecular dynamics simulation (modelled in solution) using NAMD 2.6. The conformational ambiguity of the peptide makes the structural arrangement of the peptide (and internal residues) strongly dependent on the environment. Thirteen tetra-peptide fragments of the C-terminal sequence, YEKLG-NH(2), and the corresponding tri- and di-peptide sequences were used in a fragment screen against GPa. Compound 2 (H-GPYY-NH(2)) did not give an IC(50) value, whereas PEWPSYLGYEKLGPYY-NH(2) (1) displayed an IC(50) of 34 microM against GPa. Truncated peptides derived from 1, (EKL-NH(2), EKLG-NH(2), and AcEKNH(2)) inhibited GPa (21%, 32%, 63%, respectively at 22 mM). These studies suggest key residues within the peptide chain have additional molecular interactions with GPa. The interaction of intra-sequence residues in combination with the terminal residues of PEWPSYLGYEKLGPYY with GPa may form the basis for the design of new inhibitors of GPa.

Synthesis, screening and docking of small heterocycles as Glycogen Phosphorylase inhibitors

“…1) was chosen to broaden the consideration of simple heterocycles currently reported and was based on selected variations of ring size, heteroatom substitution and synthetic accessibility. In combination and synergy with this approach, we built on our previous work where the key residues of EKL within the peptide chain of PEWPSYLGYEKLGPYY-NH 2 were identified as having additional molecular interactions with GPa [39]. Based on atom placement, bond torsion angles and synthetic accessibility, the morpholine scaffold provided a potential scaffold for mimetics of EKL, as shown in Figure 2.…”