Biomedical Engineering Reference
In-Depth Information
snugly inside the cavity of the host, and in doing so forms multiple strong cation-pi,
CH-pi, and dispersive interactions assisted by the hydrophobic effect [ 72 ].
Other synthetic hosts have recently been explored as receptors for trimethyllysine,
including macrocycle 39, which contains disulfide bridges that enable its participation
in and selection from a dynamically equilibrating host library. This aromatic-rich host
also binds trimethyllysine-containing peptides with excellent selectivities, displaying
an association constant of 40,000 M -1
50-fold
weaker binding to the unmethylated analog [ 74 ]. The affinities of both calixarene
38 and cyclophane 39 for their trimethyllysine targets are of the same order as
the naturally evolved aromatic cage proteins, which typically range from K assoc ¼
50,000-200,000 M -1 ( K d ¼
for a trimethylated peptide and
>
M). In both of these cases, protein-like affinities
and selectivities, which are rarely displayed by supramolecular hosts, are achieved.
Both receptors profit from the approach of “teaching old dogs new tricks,” i.e.,
identifying existing host scaffolds that mimic naturally evolved protein binding
partners, and using them to engage biological targets that had previously been
unconsidered by supramolecular chemistry. The creation of biomimetic receptors
for post-translationally methylated protein residues is a promising area for future
developments in biotechnology and biomedical research.
5-20
m
4 Conclusions
The technological promise of biomimetic receptor-type compounds as both sensors
and disruptors of biological pathways is only now beginning to be realized [ 67 , 75 ]
but there remain many challenges to converting this type of biologically inspired
receptor into advances that are biomedically important. The most fundamental is
that strong and specific molecular recognition in the medium of life—pure, warm,
salty water—remains difficult to achieve using the simple scaffolds that are familiar
in the world of supramolecular chemistry. Examples of success of the types
described here are relatively rare. As we continue to seek simple molecules that
can achieve complex recognition tasks, we find an almost inexhaustible source of
inspiration for these studies in the huge diversity of proteins and drugs that are
known encode strong and selective binding in water.
Acknowledgements We thank NSERC for funding. FH is a Career Scholar of the Michael Smith
Foundation for Health Research and Canada Research Chair.
References
1. Perrin CL, Nielson JB (1997) “Strong” hydrogen bonds in chemistry and biology. Annu Rev
Phys Chem 48(1):511-544
2. Xu D, Tsai CJ, Nussinov R (1997) Hydrogen bonds and salt bridges across protein-protein
interfaces. Protein Eng 10(9):999-1012
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