TY - JOUR
T1 - Synthesis of new modified truncated peptides and inhibition of glycogen phosphorylase
AU - Schweiker, Stephanie S.
AU - Loughlin, Wendy A.
AU - Brown, Christopher L.
AU - Pierens, Gregory K.
PY - 2009
Y1 - 2009
N2 - The first solution state structural analysis (NMR) of the C-terminal sequence of human GL that binds to glycogen phosphorylase a (GPa), PEWPSYLGYEKLGPYY-NH2 (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 peptidemakes the structural arrangement of the peptide (and internal residues) strongly dependent on the environment. Thirteen tetra-peptide fragments of the C-terminal sequence, YEKLG-NH2, and the corresponding tri- and di-peptide sequences were used in a fragment screen against GPa. Compound 2 (H-GPYY-NH2) did not give an IC50 value, whereas PEWPSYLGYEKLGPYY-NH2 (1) displayed an IC50 of 34 μM against GPa. Truncated peptides derived from 1, (EKL-NH2, EKLG-NH2, and AcEKNH2) inhibited GPa (21%, 32%, 63%, respectively at 22mM). These studies suggest key residueswithin the peptide chain have additional molecular interactionswith 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.
AB - The first solution state structural analysis (NMR) of the C-terminal sequence of human GL that binds to glycogen phosphorylase a (GPa), PEWPSYLGYEKLGPYY-NH2 (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 peptidemakes the structural arrangement of the peptide (and internal residues) strongly dependent on the environment. Thirteen tetra-peptide fragments of the C-terminal sequence, YEKLG-NH2, and the corresponding tri- and di-peptide sequences were used in a fragment screen against GPa. Compound 2 (H-GPYY-NH2) did not give an IC50 value, whereas PEWPSYLGYEKLGPYY-NH2 (1) displayed an IC50 of 34 μM against GPa. Truncated peptides derived from 1, (EKL-NH2, EKLG-NH2, and AcEKNH2) inhibited GPa (21%, 32%, 63%, respectively at 22mM). These studies suggest key residueswithin the peptide chain have additional molecular interactionswith 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.
UR - http://www.scopus.com/inward/record.url?scp=67649786881&partnerID=8YFLogxK
U2 - 10.1002/psc.1140
DO - 10.1002/psc.1140
M3 - Article
C2 - 19399818
AN - SCOPUS:67649786881
SN - 1075-2617
VL - 15
SP - 442
EP - 450
JO - Journal of Peptide Science
JF - Journal of Peptide Science
IS - 6
ER -