Alpha-Helix Mimetics
Mimetica’s technology can also be applied to form alpha-helix
mimetics, potentially leading to stabilised forms of helical peptide
hormones. Mimetics having a covalent hydrogen bond replacement
(Figure 1, C) can be made with Mimetica’s technology – an
approach that has not been achieved previously. Reducing this
technology to practice forms the basis of an ARC Linkage grant between
the University of Queensland and Mimetica.
Figure 1. Stabilisation of
Alpha-Helices.
A: The natural helix is stabilised by weak backbone
hydrogen bonds.
B: Side-chain to side-chain
constraints have been demonstrated in some systems, but the approach
is indirect and can interfere with receptor binding.
C: Covalent replacement of the
backbone hydrogen bond. Approach C minimizes disruptions to side
chain substituents, and is possible for the first time with Mimetica’s
technology.
Initial results have shown that one of the isomers of the macrocyclic
helical turn mimetic
with a covalent hydrogen-bond replacement
has a circular dichroism (CD) spectrum characteristic
of an alpha helix (Figure 2). This is an exciting
and significant scientific result as the mimetic is only 5 residues
long. This may be of significant commercial importance if the helical
turn mimetic can be used to stabilize truncated versions of peptide
hormones such as parathyroid hormone (osteoporosis) or GLP-I (type
II diabetes)
improving their drug-like properties.
Figure 2. Proof of concept for Mimetica’s
helical mimetics – a pentapeptide mimetic gives a distinctly
helical spectrum. This is the first reported full internal helical
mimetic.
The helical turn mimetic may also be applied to helices involved in protein-protein
interactions, such as those as illustrated below. Figure
3 shows
the helical structure (in green) of a peptide bound to a protein involved in
controlling apoptosis – programmed cell death. Blocking this interaction
is thought to be an attractive approach to treating a range of cancers. Mimetica’s
helix mimetic technology may allow the creation of shorter stabilized versions
of the peptide helix that are more likely to have drug like features of stability
and permeability than the peptide shown. Producing small molecule drugs
to block this type of protein-protein interaction has been very difficult for
traditional pharmaceutical chemistry. Our technology could enable an
effective approach to this class of targets. Another example of such
a helical interaction site is shown in Figure 4 – this is also a cancer
target.
Figure 3:
Bad peptide (helical, green) bound to the protein Bcl-xL (PDB Structure 1G5J).
Figure 4:
Helical domain of the p53 tumour suppressor protein (green) bound to the MDM2
protein with the key F19,W23,L26 residues highlighted (PDB structure 1YCQ).
To produce more drug-like mimetics of these native helical peptides the covalent
H-bond mimetic would be substituted into the centre of the helix and both ends
would be truncated and modified to optimise binding. For a Type II GPCR
hormone truncation could only take place at one end as the N-terminus is typically
required to maintain agonist potency. Truncated helix mimetics could potentially
have a molecular weight of <1000 and are likely to possess improved bioavailability.
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