Thio-Fun

The development of novel methods for site-selective functionalization of unprotected peptides and proteins under mild conditions is highly desirable. We propose herein to develop a Pd-catalyzed technique for a site-specific thioconjugation of peptides or proteins with various thiol nucleophiles, under conditions compatible with the most sensitive proteins. The centerpiece of this strategy is based on the “tag-and-modify” approach, which entails sequential installation of p-iodophenylalanine (pIPhe) as a uniquely reactive chemical group into the protein (the electrophilic “tag”, totally unreactive in the absence of catalyst) and the selective and specific modification of this group with diverse thiols. Developing such a method that can generate a non-labile C(sp2)–S bond more stable than the C(sp3)–S bonds formed in most previously reported reactions would be a major advance in the field of bioconjugation chemistry.