Insertion of achiral ω-amino acids into peptide sequences
results in replacement of scissile peptide bonds
by proteolytically stable C−C bonds. This provides a convenient
means of creating peptidomimetics. The present
study establishes the preservation of helical structures in octa- and
undecapeptides with centrally located β- and
γ-amino acids in the sequence. X-ray diffraction analyses of
single crystals and NMR studies have been used to
investigate the extent of perturbations of a regular 310-
or α-helix by the introduction of
(−CH2−)
n
groups into
the
backbone by the use of the β-Ala-γ-Abu segment (β-Ala =
β-alanine, γ-Abu = γ-aminobutyric acid), which is
formally homomorphous with a (Gly)3 segment. In
crystals, the octapeptide
Boc-Leu-Aib-Val-β-Ala-γ-Abu-Leu-Aib-Val-OMe (1) and the undecapeptide
Boc-Leu-Aib-Val-β-Ala-γ-Abu-Leu-Aib-Val-Ala-Leu-Aib-OMe
(2) retain
their helical motifs with minor bulges. Five new types of 4 → 1,
5 → 1, and 6 → 1 hydrogen bond rings are formed
with up to three extra CH2 moieties. Cell parameters
for peptide 1 are space group
P212121 with
a = 11.506 (1) Å,
b = 16.600 (1) Å, c = 27.362(1) Å, and
R = 6.1% for 2696 data measured
>4σ(F); for the undecapeptide 2,
the
space group is P21 with a = 8.605
(3) Å, b = 22.806 (4) Å, c = 19.014 (3) Å,
β = 101.47(2)°, and R = 7.5% for
3797 data measured >4σ(F). Helical
conformations in solution are also maintained for peptide 2
as is evident from
NMR studies in CDCl3, which suggest that the centrally
positioned, flexible β-Ala-γ-Abu segment can be
comfortably
accommodated into helical structures adopting gauche
conformations about specific C−C bonds of the
poly(methylene)
units. Twenty structures for backbone conformations generated from
MD simulations using NMR-derived contraints,
superpose with a low RMSD value (0.78 ± 0.05 Å), further indicating
that in these peptides the conformational
flexibility of the β-Ala-γ-Abu segment is limited and
confined to largely helical conformations.
Batrachotoxinin A, a venom from the Colombian poison arrow frog, Phyllobates aurotaenia, has been established by means of an X-ray analysis of the O-p-bromobenzoate derivative, to be 3e,9~-epoxy-14fl, 18/?-[epoxyethano-N-methylimino]-5/~-pregna-7,16-diene-3/?, 11~, 20~-triol. The material crystallizes in space group P21212a with a= 15.42, b = 7"05 and c= 26.50/~. The specialized position of the Br atom (at x, 0, 0) and the severely restricted amount of data limited the information which was available from use of the heavy atom phases. The structure was deduced by use of the tangent formula in a recycling procedure applied to partial structural information.
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