This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.It was originally believed that there were 20 amino acids from which peptides and proteins are constructed. That list has grown, including the 21st amino acid selenocysteine (Sec), structurally analogous to cysteine (Cys), the only difference being the element selenium in place of the element sulfur. Sec is ubiquitous in the 3 kingdoms of life. The human proteome includes 25 Sec containing proteins. Interest in the laboratory syntheses of peptides and proteins containing Sec has grown along with the list of structures known to contain it. During peptide/protein synthesis, the highly nucleophilic selenol (-Se-H) of Sec must be rendered inert (protected) to prevent it from reacting. At present there is only one commercially available derivative of Sec, in contrast to the 10 plus derivatives of Cys with distinct protecting groups on the thiol. Multiple selenol and thiol protecting groups are essential to the syntheses of complex peptides that contain 2 or more crosslinks (-S-S-, -Se-Se- and/or -Se-S-). The specific goals of this project are to synthesize, purify, and characterize new Sec derivatives with different selenol protecting groups and then to use the new derivatives in the syntheses of increasingly complex peptides to demonstrate their utility. During summer 2005, the PI and an undergraduate student synthesized and characterized the new compound bis(N-9-fluorenylmethoxycarbonyl)selenocystine (a diselenide), a molecule that will serve as a precursor to several Sec derivatives. Since last summer, the PI has scaled up that synthesis, improved the synthetic yield, optimized the purification conditions, and is working on the synthesis of one target derivative. In order to check the purity of the starting diselenide and monitor the course of the synthetic steps, the PI has worked out separation conditions on a high performance liquid chromatograph. The target derivative appears to be present in a reaction mixture that contains significant starting diselenide. Optimizing the synthetic steps is in progress.
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