This proposal requests funding to extend studies of tryptophan dimerization to bioactive peptides and proteins. Formation of tryptophan dimers has two important consequences which may be exploited in the treatment and understanding of diseases at the molecular level. First, tryptophan dimerization has the potential to constrain peptide conformation. Conformational constraints have the potential to increase the activity of peptides and peptidomimetics. Second, the bisindole linkage is highly fluorescent. This kind of intrinsic fluorescent probe may be useful for studying biological events such as binding and conformational changes. The PI has shown that he can form tryptophan dimers in simple peptides using acid- promoted Mannich reactions. This proposal requests funding to continue these studies by introducing tryptophan dimers into complex bioactive peptides and proteins. Specifically, he will optimize the chemoselectivity of tryptophan dimer formation, cleavage and oxidation, study the relationship between conformation and fluorescence of tryptophan dimers, determine context effects in chromophore formation via combinatorial chemistry, and finally, extend this chemistry to bioactive peptides and hen egg white lysozyme.
| Dinh, T D; Van Vranken, D L (1999) Control of ditryptophan cross-linking: dihydrotryptophan as a tryptophan precursor in peptide synthesis. J Pept Res 53:465-74 |
