Other Therapeutic Applications of Coiled Coils

Owing to their structural versatility, stability, and specificity, leucine zippers and other coiled coils have gained widespread attention as potential tools and building blocks for a number of model applications. Contegno et al. (2002) proposed a generalized method to inactivate self-associating molecular targets by creating a chimera of a coiled-coil domain and the selected target, creating interaction sites at both ends of the molecule. Because of the bifunctionality of the chimera, this leads to the formation of large-molecular-weight complexes and consequent inactivation of the target molecule. However, it is not clear from this work whether the chimera is stable in solution by itself or its application has to rely exclusively on genetic methods.

Coiled-coil systems have been considered as drug-delivery vehicles for the controlled release of drugs. An interesting approach to the reversible formation of a hydrogel has been described. An artificial recombinant polypeptide consisting of coiled-coil oligomerizing sequences and an unstructured part of hydrophilic amino acids with large solvent retention functionality was constructed. Oligomerization via the coiled-coil region leads to formation of a hydrogel. Changes in pH or temperature lead to dissociation of the coiled-coil oligomers and dissolution of the hydrogel (Petka et al. 1998).

The specificity of coiled-coil oligomerization has also been used in drug targeting. In an approach known as pretargeting, a targeting compound, e.g., an antibody, is fused to a heterodimerizing coiled-coil sequence. The therapeutic agent, e.g., a radionuclide-chelate complex, is equipped with the complementary coiled-coil sequence. Administration of the targeting compound specifically labels the therapeutic target. Subsequent administration of the therapeutic agent and formation of the heterocomplex lead to targeted delivery of the drug to the site of interest. This is expected to increase therapeutic efficiency and reduce unwanted side reactions (Goodwin and Meares 2001; Goldenberg 2003). An advantage of using coiled-coil sequences for this approach is their small size with no concomitant loss of specificity.

Acknowledgements We thank Dr. Rudolf Volkmer, Dr. Michael Portwich, and Carsten Mahrenholz for stimulating discussions and Carolyn Vargas and Anja Sieber for helpful comments on the manuscript.

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