Due to their intrinsic properties, such as their potential for highly specific interactions with target molecules, generally low toxicity and immunogenicity, and rapid clearance, synthetic peptides are gaining increasing attention as candidates for new drugs. This is especially true for the development of inhibitors of protein-protein interactions, where peptides typically cover large protein interface regions better than small molecules.
On the other hand, synthetic peptides also have serious bottlenecks that need to be considered and, if necessary, addressed in the development of peptide drugs. The biggest challenge is obviously the limited metabolic stability of peptides, as they are rapidly degraded by proteolytic enzymes, precluding oral administration of peptide drugs. This challenge can be addressed in different ways. First, unlike recombinant protein synthesis, chemical peptide synthesis is not limited to protein amino acids as building blocks. A large number of additional amino acids are currently available for chemical peptide synthesis. In addition to significantly increasing the metabolic stability of the peptides, the incorporation of these amino acids also increases the chemical diversity presented by the synthetic peptides, as these additional amino acids introduce chemical moieties not provided by protein amino acids. Furthermore, stabilizing the conformation by cyclization or by introducing defined secondary structures has been shown to protect peptides from proteolytic enzymes. This shielding effect can also be achieved by coupling peptides to larger inert molecules such as polyethylene glycol.
Due to their molecular size, peptides are rarely able to pass passively across cell membranes, limiting their application to intracellular target molecules. However, this disadvantage can be counteracted by linking the drug peptide to one of a large group of available cell-penetrating peptides capable of transporting various molecular cargoes into cells.
In general, synthetic peptide chemistry via solid-phase synthesis is fairly simple and has been optimized over the past few decades so that almost all peptide sequences are available synthetically today. However, in our experience, specific synthetic peptides may require the use of specific protected amino acids and other building blocks, solid supports, linkers and other reagents, which obviously increase the cost of synthesis. These considerations may be relevant for large-scale synthesis of peptide drugs as well as peptide biomaterials.
The design of peptides as inhibitors of protein-protein interactions is often based on the solved 3D structures of the respective protein-protein complexes. While such structures are increasingly obtained by powerful X-ray crystallography techniques, their generation is not trivial and depends on the availability of suitable crystals of protein complexes. Overall, we strongly believe that the importance of synthetic peptides in biomedical research as well as in biomaterial engineering will continue to grow in the future, considering the tremendous technological and scientific advances in the field of using peptides as protein mimetics.