Biomedical Engineering Reference
In-Depth Information
(SAR) studies of the linear ligands, starting from the natural
α
-melanocyte stimulating hormone
-MSH and then to the cyclized
ligands (Figure 8.6, MT-II and SHU9119). Melanocortin receptors are involved in many critical
physiological actions such as pigmentation, feeding behavior, and sexual behavior. As shown in
Figure 8.6, MT-II and SHU9119, bear the lactam ring using the side chain groups of lysine and
aspartic acid. SHU9119 was derived from superagonist MT-II, by the replacement of the amino acid
d-phenylalanine to d-2
(
α
-MSH), which led i rst to a potent and stable linear peptide NDP-
α
-naphthylalanine. This introduction of four carbons (a local modii cation) on
the side chain of the phenyl ring led to SHU9119, a superpotent antagonist at the melanocortin 3 and
4 receptors, which demonstrates the drastic change in biological action that a small change in struc-
ture can induce. Cyclic RGD analogues are a class of
′
3
antagonists and are of particular interest
in human tumor metastasis and in angiogenesis. Kessler's group has demonstrated an excellent
example of N- to C-terminal cyclized bioactive peptides. Incorporation of d-amino acids to induce
a
α
v
β
3
antagonists.
Examples of side chain to the C-termini are well demonstrated by Schiller's group in exploring
opiate receptor selectivity by altering the conformational restriction on the modii ed enkephalin
sequences. The series of cyclic enkephalins that were synthesized exhibited the subtle variation in
conformational restriction thus disclosing the conformational space exhibited by the opiate recep-
tors. Many other constraining moieties exist including alkylation,
trans-
guanidation, acylations,
thioether bridges, and metal complexed peptides, are not discussed here (Figure 8.7).
β
-turn structure within the cyclized moiety has resulted in very potent
α
v
β
8.3.1.3
b
-Turn Peptidomimetics and Other Peptide Mimetics
β-Turn structures are an important class of peptides and are recognized by many GPCR's for
their afi nity and potency. Besides the aforementioned strategies of globally restricting dynamics
of a peptide, enhancing β-turns also provides an excellent opportunity for design of novel bicyclic
conformations. A β-turn can be viewed as a 10-membered ring formed from four amino acids that
are stabilized by a hydrogen bond between the carbonyl group of the i rst amino acid residue and the
amine-hydrogen of the fourth amino acid residue. When such interactions are stabilized by inducing
greater constraints on the second and third amino residues can lead to novel templates for β-turn
peptidomimetics.
The development of peptide mimetics can be a critical drug discovery strategy. The evolution of
peptide ligands to small molecule mimetics has been a major goal in the i eld, with several notable
successes. Peptides are ideal drug leads, but often their stability to proteolytic enzymes and their
bioavailability need to be enhanced. This can be done by incorporating various computational tools
for molecular design, proprietary scaffolds, conformational constraints, conformation-activity
analysis, and lead optimization strategies to design mimetics that will retain the desired biological
properties of the peptide lead, but are metabolically stable, have appropriate diversity, and can be
tailored to have desired drug-like pharmaceutical properties. The peptide mimetic design strategies
are summarized in Figure 8.8. The interaction of a peptide with a receptor/acceptor may occur via
a direct binding of a linear sequence of the peptide in one of the conformations accessible to a par-
ticular peptide. Linear peptides are the mode of recognition of many peptide ligands for receptors/
acceptors. In other cases, turn structures or cyclic structures are important, as in MTII, where
the -His-d-Phe-Arg-Trp- peptide sequence is oriented in a turn motif. In larger peptides or proteins,
the folding of the peptide may bring groups that are distant in a sequence into close spatial arrange-
ments, and thus the “binding motif” is a 3D arrangement of the peptide side chain groups involved
in recognition. In other cases, the recognition may be along a face of a β sheet or α helical sequence.
The linear, folded, and 3D presentations can all be translated from peptides to peptide mimetics.
8.3.1.4 Applying Computational and Biophysical Studies for Design
Rational design should be and is currently a central theme for drug discovery. Experimental and
theoretical developments in peptide chemistry and biophysical methods, in conjunction with new
biological methods have offered a wide variety of new design, synthesis, and analysis methods for
