Drug Delivery Opportunities

Therapeutic drugs based on naturally occurring peptides and protein fragments offer attractive alternatives to non-peptidic drugs, due to high and very specific activity, and in most cases, low toxicity of these native molecules. In the past couple of decades significant efforts were devoted in both academia and industry to optimize the in vivo biological properties of peptidic drug leads and their peptidomimetic derivatives, without much success. According to Chaperone's cell penetration assays, labeled versions of the native antibacterial peptides pyrrhocoricin, drosocin and apidaecin enter Escherichia coli cells and mouse macrophages. Therefore, if the antibacterial peptides or their delivery units are co-synthesized with other drug leads, pyrrhocoricin or drosocin can facilitate the penetration of these other drug leads into mammalian cells. Ultimately this system can be used to make any drug lead orally available. Chaperone is trying to provide a generally applicable system for the oral delivery of peptidic and peptidomimetic drug leads developed at other biotechnology or pharmaceutical firms.

Image from Gallo and Huttner, J. Invest. Dermatol. 1998

Antibacterial peptides are not the only polyamides that can penetrate into cells. Except for helical signal-sequence based peptides, the common structural characteristic of the competing protein fragments and synthetic constructs is the abundance of positively charged amino acid residues, arginine and lysine, making these peptides often capable of binding to not only negatively charged membrane surfaces but nucleic acids as well. However, increasingly efficient cell penetration is often accompanied by destruction of the cell membrane, and hence, toxicity. Remarkably most of the alternative cell-penetrating peptides lack proline residues known to break helices, and indeed they are helical in membrane environments. In contrast, pyrrhocoricin and drosocin fail to form helical structures. Apparently the positive charges in the short, proline-rich antimicrobial peptides enhance bacterial and mammalian cell entry, and the interspersed prolines may prevent helix formation and toxicity to the host.