Molecular recognition plays an important role in biological processes. In
general, it involves fairly weak interactions between individual molecular
fragments. However, markedly strong bonds are occasionally observed, such
as those between
antibodies and their
antigens. One reason for this seems
to be that antigens can have multiple binding sites, to which multiple
antigen-binding sites in the antibody can bind at the same time. This once
again demonstrates that the whole can be more than the sum of its parts;
the multiple interactions are stronger than would be expected from the
corresponding individual bonds. In addition, the specificity of the
molecular recognition is higher. Researchers wish to use this phenomenon,
known as multivalency, for the development of pharmaceuticals and
targeted-imaging agents. "The idea is to attach several pharmacologically
active peptides or proteins to a scaffold in order to present the target
molecule with multiple binding sites,! which should increase the
selectivity and strength of the binding," explains E. W. "Bert" Meijer.
Meijer and his team of scientists from the Universities of Eindhoven,
Utrecht, and Maastricht chose to use
dendrimers as scaffold molecules.
Dendrimers are spherical, highly symmetrical molecules with cascading
branches. As with a tree, the central trunk of the molecule holds branches,
which then continue to branch out further and further. The researchers in
the
Netherlands thus needed to produce dendrimers with proteins attached to
the tips of their branches.
However, the researchers found a generally applicable strategy, a method
called Native Chemical Ligation, by which protein fragments can selectively
and spontaneously be hooked together to form "natural"
Peptide bonds. In
order for this to work with dendrimers, the tips of the branches must be
equipped with special functional groups. The proteins and peptide chains
must then be attached to the required complementary fragment.
If an excess of dendrimer is then allowed to react with a low amount of
protein, dendrimer molecules are formed that contain exactly one protein
molecule each. Subsequently, more branches can be equipped with
proteins?either the same kind or a different sort. The number of proteins
attached depends on the size, form, and, of course, the number of branch
tips on the dendrimer. "Our method offers access to a broad palette of
precisely defined multivalent peptides and proteins," says Meijer. "This
allows for the systematic investigation of multivalent biological
interactions."