Robert F. Standaert

Associate Professor

Organic

My group's research falls at the interface of chemistry and biology; we combine the tools of organic synthesis, protein biochemistry, and molecular biology to explore and manipulate biological systems. At the experimental level, most of our work involves the chemical synthesis of unusual amino acids, peptides, and peptidomimetics, whose interactions with proteins or whole cells we go on to study. We have two main areas of interest:

Nuclear Protein Transport

Moving messenger proteins back and forth between nucleus and cytoplasm is an integral part of the communication system cells use to control their actions (divide or stop dividing, turn genes on or off, and so on). We have several efforts aimed at understanding and manipulating this system, the following two of which are most advanced:
Photo-regulation of nuclear protein transport. We seek to direct the movement of proteins within a cell from the outside using light. A protein destined for the nucleus usually has a distinctive feature called a nuclear localization signal (NLS), which is recognized by a specific receptor (a protein called karyopherin a ). We have created many variants of the NLS into which we have installed a photo- isomerizable amino acid (see figure, left box); these were screened for differential binding of the peptide photo-isomers to karyopherin a in vitro, and at present, we have an excellent candidate which is being tested for its ability to control protein movement in cells.
NLS Mimetics. There are actually several slightly different types of karyopherin a in mammalian cells, and in order to learn more about the detailed structural features recognized by each, we have created simple, non-peptidic mimics of the NLS. The compound shown in the figure (upper right box), for example, has biologically useful affinity for the a2 form of karyopherin. We are initiating tests with the other karyopherin forms.

Translatable Amino Acid Analogs

Natural proteins are assembled from just twenty amino acids specified by the genetic code, and there is considerable interest in expanding this pool to create proteins with new properties. One approach is to identify close structural analogs of the genetically encoded amino acids that microorganisms' translational machinery will accept; if the organism is cultured in the presence of the analog, the analog will be incorporated into the proteins made by the organism. Our specific interest is in the unusual amino acid furanomycin, an analog of isoleucine (figure, lower right box). We have executed a modular and concise total synthesis of furanomycin that provides ready access to furanomycin and variations of it, and we are exploring the ability of these compounds to substitue for isoluecine in bacteria and yeast.