Over the past decade, as the pharmaceutical industry has begun to recognize the role that peptide therapeutics can play in addressing unmet medical needs, and how this class of compounds can be excellent supplements or even the preferred alternative to small molecule and biological therapies.
We think of peptides as any polyamide (even biopolymers with esters, thioesters, or other modified backbones) that can be made on a modern chemical peptide synthesizer. The high specificity and low toxicity of polypeptide drugs stem from their extremely tight binding to the target. This is due to the large chemical space covered by side chain variation of natural amino acids. The current database estimates the total number of active protein-ligand binding sites to be 7700. Calculations based on 17 variable residues showed that an 83,000-member tetrapeptide library could be made that covers essentially all unique protein binding regions. Since the median length of the active site is 11 amino acid residues, the designed ligand should also be longer. Hundreds of appropriately protected and activated non-natural amino acid derivatives, ready for incorporation into synthetic peptides, are commercially available and indeed frequently explored in peptide-based polypeptide drug design.
The permeability of peptide drugs across biological barriers can be improved by adding modules for passive or active transport. The addition of positively charged amino acids, especially at the terminal positions, can improve the cell and tissue permeability of the peptide. Repeated arginine-containing modules even contribute to in vitro nuclear uptake or in vivo bioavailability. One problem is that polycations frequently disrupt mammalian cell membranes, as shown by the toxicity of natural or engineered antimicrobial peptides containing large amounts of lysine and arginine. Presumably, a safer solution would be to bind the therapeutic peptide to a ligand for a cell surface receptor.
Since the introduction of insulin nearly a century ago, more than 80 peptide drugs have entered the market to treat a variety of diseases, including diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection and chronic pain. In this outlook, we summarize key trends in peptide drug discovery and development, covering early efforts focusing on human hormones, elegant medicinal chemistry and rational design strategies, peptide drugs derived from nature, and major breakthroughs in molecular biology and peptide chemistry. We highlight lessons learned from earlier approaches, which are still relevant today, and emerging strategies, such as integrated venomomics and peptide display libraries, creating new avenues for peptide drug discovery.