This award by the Chemical Structure, Dynamics and Mechanisms Program of the Chemistry Division supports the efforts of Professor Ronald Breslow of Columbia University to study catalysis within the interiors of macromolecules. There are many advantages to these enzyme mimics, including the ability to organize well-defined three-dimensional structures around the reacting species. Professor Breslow and his group prepare polymers containing imidazole sidechains that are even more effective than the best previously-studied polyamines. The group also studies new polymers, including some with very highly defined sizes and shapes. These new polymers are used as mimics for biological reactions that use thiamine pyrophosphate as a coenzyme in processes that are central to life. The catalysts are used for cleaving RNA.
In a second project, Professor Breslow and his group develops evidence about how amino acids, nucleosides, and sugars form on prebiotic earth. This work addressed the formation of chiral structures, one of the great unsolved mysteries in science. A major goal of modern chemistry is to be able to predict the properties of unknown compounds reliably. Professor Breslow's research group and collaborators from Columbia University's Chemistry Department develop computational methods to quantitatively predict the extent to which reactions that establish handedness perform. Their methods predict unknown chemistries that could lead to useful synthetic processes for manufacturing medicinal compounds.
This research program show how reactions perform in water taking advantage of hydrophobic binding while avoiding the problems that water can cause when it binds to catalytic groups and substrates. The artificial enzyme systems expand the field of chemistry to include processes in which multiple components are spontaneously bound to a catalyst, as happens with natural enzymes. Water is an environmentally benign solvent and is of great interest as a component of Green Chemistry.
The processes of life are in general performed with the help of enzymes--proteins that speed up the desired chemical reaction and are selective in speeding up only the reaction that is needed for life. Chemists, including biochemists, have learned how many of these enzymes work, so a field called "biomimetic chemistry" (a phrase invented by the awardee) has developed in which chemists take the lessons from the chemistry of life and use those lessons to make new chemical catalysts to perform useful chemical reactions. In this project the goal has been to create catalysts that can perform useful processes acting as medicines. The result would be a new class of medicines, those that do not simply modify biological processes but actually imitate enzmes. In addition, the goal is to make these new medicines selective so as to destroy undesirable toxic metarials such as viruses that attack humans, while being selective and not harming the normal materials of human life. The principal investigator (PI) of this grant has in the past studied chemistry that can destroy RNA by cleaving it. In this project he has created new catalysts that 1) bind to RNA, and 2) cut it into pieces. The new catalysts are not proteins, which have many disadvantagrs as potential medicines, but are simple stable chemical compounds much smaller than the natural catalysts. The lesson comes from the natural enzyme Ribonuclease A, a protein that uses the sidechains of the protein with histidine groups that can act as both acids and bases in performing the cleavage. His new catalysts have many positive charges that lets them bind to RNA (which has many negative charges) and it also has imidazole groups, the same groups found in the protein Ribonuclease A. The positive groups of the new catalysts act as acids while the imidazole groups act as bases. In a published account the new potential medicines are flat while in the still unpublished work the potential medicines are of two classes, right-handed and left-handed. In the new work the left-handed are better, because thay bind better to the (right-handed natural) RNA. In future work it is planned to attach a piece of RNA to the catalysts so as to give them selectivity in cutting the RNA of viruses while protecting the natural RNA of humans.
