Chimeric peptides are multifunctional drug formulations. Therefore, in linking a drug to a transport vector, it is essential that the bifunctionality of the conjugate be retained. This can be achieved in one of two ways. First, the drug and vector may be conjugated via a noncleavable (amide) linker in such a way that the biological activity of both components is retained. Second, the drug and vector may be conjugated via a cleavable (disulfide) linker, and the biologic activity of the drug may be lost when the drug is in the form of the chimeric peptide. However, the biologic tivity of the drug may be restored following cleavage of the drug from the conjugate. Therefore, there are multiple approaches to the creation of multifunctional chimeric peptides and the diversity of the molecular formulations is outlined in Figure 6.1.
The construction of a chimeric peptide starts from three separate platforms that must be given simultaneous consideration. First, a vector discovery program must be initiated for the discovery of species-specific blood–brain barrier (BBB) transport vectors, such as those reviewed in Chapters 4 and 5. Second, the linker strategy must be developed and this might use chemical conjugates, genetically engineered fusion proteins, avidin-biotin technology, pegylation technology, or liposome technology (Figure 6.1). The linker strategy may employ cleavable linkers such as disulfides, or noncleavable linkers such as amides or thioethers. Within the noncleavable amide linker category, the linker may be short, e.g., 14–20 atoms, or extended, e.g., >200 atoms in length. The third area that must be considered is the pharmacokinetics and metabolic stability of the conjugate in vivo.