M. Chorev et al., CIRCULAR-DICHROISM (CD) STUDIES OF ANTAGONISTS DERIVED FROM PARATHYROID HORMONE-RELATED PROTEIN, International journal of peptide & protein research, 42(4), 1993, pp. 342-345
We have undertaken a study of the structure of antagonist peptides der
ived from the parathyroid hormone-related protein (PTHrP) in the prese
nce of amphiphiles using circular dichroism (CD). The results were use
d to gain knowledge about bioactive conformations of the peptide when
bound to a membrane. The substitutions within the PTHrP-(7-34)amide se
quence resulted in differences in biological activity. Structural dete
rmination by CD showed the presence of an alpha-helical structure. The
antagonist activity was increased in constrained peptides in which i
to (i + 4) side-chain to side-chain cyclization was used to form a lac
tam, [Lys13,Asp17]PTHrP-(7-34)NH2. This peptide showed increased helic
ity in the presence of a surfactant. Hydrophobic substitutions Leu and
D-Trp at positions 11 (Lys) and 12 (Gly), respectively, in PTHrP-(7-3
4)NH2 resulted in increased potency, but the derivatives were not sign
ificantly more helical than the unsubstituted peptide in the presence
of surfactants. The combination of the hydrophobic substitutions with
the constraint of lactam formation were mutually exclusive in terms of
their biological activity and their alpha-helical content. We conclud
e that hydrophobic substitutions contribute to an increase in binding
affinity by increasing hydrophobic interactions which stabilize recept
or-ligand complexes. Structural rigidification, on the other hand, inc
reases the alpha-helical content, which is important for attaining a c
onformation recognized by the receptor. (C) Munksgaard 1993.