Editorial [ Are Peptide Therapeutics the Future? Guest Editor: Sivaram Pillarisetti ]

Small Molecule Versus Peptides The following is an excerpt from C&E News Volume 83, Number 11 pp. 17-24. Imagine a conversation between a small molecule and a peptide on a make-believe pharmacological playground. The small molecule would tout its virtues of small size, low price, oral availability, ability to cross membranes, and straightforward synthesis. The peptide would respond: "True, I may be bigger, more expensive to synthesize, and less stable than you. I may clear faster from the body and usually need to be injected rather than swallowed as a pill. But I can be much more potent, show higher specificity, and have few toxicology problems. I also don't accumulate in organs or face drug-drug interaction challenges like you do. So there. Small molecules have been the choice of drug for two important reasons. 1) ease and low cost of synthesis and 2) stability and therefore longer half life. However, toxicity is a major cause of failure for new drug candidate and Pharma Industry productivity. Many promising new drug candidates that show excellent efficacy in preclinical animal models fail when it is found that they cause toxic effects in humans. This is one of the reasons that the pipelines of many pharmaceutical companies are quite thin; and in contrast the pipeline of biologics is steadily growing. Although it is hard to pin point the reasons for such adverse effects, it is conceivable that small molecules by virtue of their size could potentially interact with multiple targets and accumulate in tissues. Despite applying stringent screens and rational drug design it is often difficult to predict how a small molecule interacts with different proteins in real life scenario. This is especially true if target protein belongs to a family of closely related proteins, e.g. kinases, matrix metalloproteinases. Such promiscuity often a cause for concern from safety view point however, may turn out to be useful when results in pleiotropic effects. Aspirin for example has many pharmacological effects most of which are beneficial. Statins, although targeted for HMG-CoA reductase inhibition and cholesterol lowering, interact with other targets which may explain some of their anti-inflammatory effects [1]. Methotrexate a widely used drug in cancer and inflammatory diseases has multiple mechanisms of action [2, 3]. Selectivity/high specificity may be the greatest advantage of proteins (peptides) over small molecule drugs. Biologics traditionally have not shown non-specific effects typical of small molecule drugs. Successful examples include TNFα blockers used in rheumatoid arthritis and related inflammatory diseases (e.g. Enbrel, Remicade and Humira), VEGF inhibitor Avastin for colorectal cancer, therapeutic proteins such as insulin, granulocyte-colony stimulating factor and erythropoietin. Not surprisingly there has been a shift towards biologics in the pharmaceutical industry. Although Protein therapeutics do not have the disadvantages of small molecule drugs, they have their own issues. They are all injectable drugs and therefore injection site reactions are a common occurrence. Immunogenicity is often a problem with many protein therapeutics. Protein Activity can be Mimicked by Peptides Although proteins are large molecules, the active site/moiety of a protein involve only a few amino acids. Thus a peptide derived from this region could potentially act as an agonist or antagonist. It is also possible to mimic the function of a protein by a stretch of amino acids that have a different sequence yet retain conformational similarity to the active site of the native protein. Phage display is a technology platform now widely used to identify peptide agonists and antagonists. Phage display makes large-peptide diversity libraries readily attainable for identifying novel peptide ligands for receptors and other protein or non-protein targets [4]. This technology is based on the idea that large protein-protein interaction surfaces (epitopes) can be distilled down to small pharmacophores. These may be accessible to scaffolding, yielding new orally active drugs that might otherwise have taken greater time and effort to be discovered through chemical-library screening (see Fig. 1). Vast libraries of peptides can be created through cloning of complex mixtures of combinatorially synthesized oligonucleotides into specialized expression display vectors. An example is the filamentous phage display system whereby the expressed peptides are displayed as fusion to phage coat proteins. Affinity purification of the phage on the target protein is then used to recover peptides with binding activity. Sequencing the appropriate segment of the DNA of each captured phage provides the primary sequence of peptides that bind the target. This technology has been used to generate peptide mimetics of structural proteins, hormones and growth factors and peptide inhibitors of enzymes [5,6].........