Biomedical Engineering Reference
In-Depth Information
about the functional groups and their orientation, which are essential for
interaction with the receptors or enzymes, allowing further reduction of
the
peptide
character
of
the
molecules,
ultimately
resulting
in
peptidomimetics.
3.4
SECONDARY STRUCTURE MIMICS (EXCLUDING
TURN MIMICS)
Within proteins and peptides, secondary structure elements such as
a-helices, b-turns and b-strands determine the 3D orientation of the side
chains. These secondary structure elements are recognition motifs for the
interaction with other proteins, receptors and enzymes. Short peptide
sequences corresponding to the helical or b-sheet regions of proteins gen-
erally have only low populations of conformations corresponding to an a-
helix or b-strand. Given the general flexibility of a peptide, it is important
to stabilize, or fix, the conformation which interacts with the receptor
protein. The minimization of the entropy penalty for adopting the bioac-
tive conformation generally results in a higher affinity. Mimicking the
functional helix or sheet region of a protein by appropriate mimetics allows
the preparation of protein mimetics with a much reduced size and better
synthetic accessibility [209].
In order to induce secondary structure in peptides, amino acids
with known propensities to adopt various secondary structures are
often used, as explained in the previous sections on for instance the
propensity of a,a-disubstituted amino acids to induce helices. A second
approach is to use 'nucleators' of secondary structures. Such nucleators
are responsible for inducing for instance a b-sheet or a-helical structure in
the peptide that is appended to them. The design and synthesis of struc-
tures that mimic the secondary structure of a peptide or protein is a very
active field of research. Given the importance of turn structure for recep-
tor recognition, extensive research efforts have been and are still being
devoted to the development of turn mimics.
3.4.1 b-strand Mimetics
In an extended b-strand, the peptide backbone is in a fully extended
conformation; the side chains of contiguous residues are presented on
alternating sides of the strand. The amide NH and CO groups are exposed
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