Human diseases caused by an excess of protein function can often be treated effectively using small molecules that bind to the offending proteins and turn them off. In contrast, diseases caused by protein deficiencies are generally refractory to this approach, and thus most of these diseases remain incurable. To address this challenge, my research program aims to advance the frontiers of pharmacology toward molecular prosthetics, i.e., the use of functional small molecules as substitutes for proteins that are missing or dysfunctional in currently incurable human diseases. In this context, my students and I focus on the synthesis and study of small molecules that perform higher-order, protein-like functions.
The ion channelforming antimycotic amphotericin B is a natural prototype for small molecules that replicate the functions of protein-based ion channels. Such compounds may one day provide new treatments for human channelopathies such as cystic fibrosis. However, despite more than five decades of research, the archetypal amphotericin B ion channel remains poorly understood at the molecular level. For decades the leading model predicted that the amphotericin B ion channel is stabilized primarily by a ring of salt bridges at the channel periphery between oppositely charged carboxylate and ammonium ions. Many studies have attempted to probe the importance of these two groups via their covalent modification. The self-assembly of small molecules can be exquisitely sensitive to steric effects, however, and this phenomenon may complicate this approach. My group therefore pioneered an alternative strategy that involves synthetically deleting chemical groups appended to the macrolide skeleton in a systematic way and then determining the consequences of these deletions. This approach has already led to our discovery that, contrary to the current channel model, this ring of salt bridges is not required for potent antifungal activity.
Building on this discovery, an efficient and flexible total synthesis of amphotericin B stands to enable the first systematic dissection of the structure-function relationships that underlie its extraordinary ion channel activity. To enable these types of experiments, my research group is developing new strategies and methods to make the process of complex small-molecule synthesis as simple, efficient, and flexible as possible. In this regard, modern peptide synthesis, involving the iterative coupling of bifunctional amino acids, is an inspiring benchmark. Amino acidbuilding blocks are now commercially available in suitably protected form as stable, crystalline solids, and the process of peptide synthesis is routinely automated. As a result, this highly enabling methodology is accessible to a broad range of scientists.
In sharp contrast, the laboratory synthesis of small molecules remains a relatively complex, arduous, and nonsystematized process practiced almost exclusively by highly trained specialists. This severely restricts the maximum utilization of small molecules in science and medicine. To overcome this barrier, my students and I have pioneered a simple and highly modular strategy for making small molecules that is analogous to peptide synthesis and involves iterative cross-coupling of bifunctional haloboronic acids. To avoid random oligomerization of such a bifunctional reagent, my group discovered a chemical switch for turning the boronic acid functional group off and on. This switch is based on the tridentate ligand N-methyliminodiacetic acid (MIDA), which promotes the reversible rehybridization of a boronic acid from trigonal planar (on) to pyramidal (off) under very mild conditions. In this iterative cross-coupling approach, building blocks are used that have all of the required functional groups preinstalled in the correct oxidation state and with the desired stereochemical relationships. These building blocks are then brought together via the recursive application of one mild reaction. Our MIDA boronatebuilding blocks are invariably air-stable, highly crystalline, environmentally friendly solids that can be elaborated or cross-coupled efficiently.
These discoveries have already led to the commercial availability of a large collection of our MIDA boronates for widespread utilization in small-molecule synthesis. This chemistry is being utilized in many pharmaceutical companies throughout the world to facilitate the search for new medicines. Our long-term goal is to build a machine with the capacity for fully automated construction of a broad range of biologically active small molecules from simple and readily available building blocks, thereby making the powerful discovery engine of small-molecule synthesis widely accessible to the nonchemist.
My research team recently discovered that this iterative cross-coupling approach is a promising strategy for preparing amphotericin B and other naturally occurring small molecules with the capacity for higher-order protein-like functions. We are now harnessing the efficiency and flexibility of this new chemistry to dissect systematically the structure-function relationships that underlie the extraordinary activities of these prototypical small molecules. Our combined efforts in small-molecule synthesis and function seek to build a strong foundation for the development of molecular prosthetics as a powerful and general strategy for the understanding and betterment of human health.
Grants from the National Institutes of Health, the National Science Foundation, and the American Chemical Society provided partial support for these projects. Additional support was provided by the Camille and Henry Dreyfus Foundation, the Arnold and Mabel Beckman Foundation, the Alfred P. Sloan Foundation, Bristol-Myers Squibb, Amgen, AstraZeneca, Sigma-Aldrich, and the University of Illinois at Urbana-Champaign.
As of May 30, 2012