Angewandte Chemie International Edition
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Angew. Chem. Int. Ed. ,
Branched Molecule acts as Carrier for Multiple Proteins—A New Approach to the Production of Multivalent Drugs
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—no easy task.
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.”