From Tens to Trillions - Advances in Synthetic Combinatorial Chemistry of Peptides, Peptidomimetics and Heterocyclic Compounds Derived from Peptides

Introduction An important shortcoming in contemporary biomedical research has been the lack of substantive progress in reducing the cost and time, while ultimately increasing the success rate of drug discovery. In spite of the many advances in technology and basic understanding over the past decade, surprisingly little increase has occurred in the number of new drugs available. This problem has resulted in the longstanding and continuing reality in the pharmaceutical industry that new drugs coming into the marketplace are often mere modifications of existing chemical entities (“me too drugs”), rather than truly novel compounds that are actually optimal or unique to the target of interest. The revolutionary advances in combinatorial chemistry over the past 20 years now enable extremely large numbers of individual compounds to be synthesized. This has fostered a simple volume-driven approach not greatly different from that utilized for the past 50 years, but which in turn has several of its own challenges. The first involves the extremely large number, manner and format of compounds to be prepared and screened. The second involves the type(s) of assays with which these compounds can or should be used, and how the compounds should be tested in such assays. Both of these factors typically hamper academic and non-profit research organizations. It started with peptides! Over the course of the past 20 years, our group has been consistently working toward the development of new techniques to discover simple solutions or approaches to complicated concepts or methodologies. To this end, we have directed our efforts toward the conception and development of novel approaches that permit the simplification of synthetic and screening processes of value to the drug discovery process. These efforts have resulted in the development of five key technologies: (1) the “tea bag” method for solid phase synthesis [1]; (2) the use of “mixture-based” combinatorial libraries to identify highly active individual compounds from literally millions of others [2]; (3) the use of “positional scanning” approaches for the rapid identification of individual compounds from highly diverse mixture-based combinatorial libraries [3]; (4) the “libraries from libraries” method for the generation of very large acyclic and heterocyclic combinatorial mixture-based libraries [4]; and (5) the solid phase synthesis on “volatilizable” solid supports and linkers that can be completely removed by their ultimate decomposition and ultimate “volatilization” during the final cleavage step of the synthetic process [5].