The hitchhiker´s guide to chemoselectivity in chemical protein synthesis

Posttranslational modifications (PTMs) allow proteins to perform a variety of physiological functions. Thus, it is of prime importance to elucidate their role on proteins in physiological and/or pathophysiological processes. However, molecular biological methods to generate proteins either does not yield in proteins with PTMs (E. coli) or give rise to heterogeneous mixture thereof (mammalian cells). To provide homogeneity, different chemoselective ligation methods such as native chemical ligation (NCL) were used successfully to associate peptide segments and install PTMs in a site-specific manner to proteins. In this contribution, I will give an overview on new methodologies to expand the chemoselective synthetic toolbox for chemical protein synthesis. Especially, site-specific lipidation (Huang et al. Angew. Chem. Int. Ed. Engl. 2019) and SUMOylation (Dardashti et al. Chem. Eur. J. 2020) of proteins will be presented. Hereby, not only NCL, but also Ser/Thr-Ligation (STL) will be discussed. Moreover, new backbone modification methods as well as Fmoc-SPPS building blocks orthogonal to STL and NCL will be introduced.

Milkyway Image by Beate Bachmann by Pixabay

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Contributed by Can Araman

Can Araman completed his PhD degree under the supervision of Prof. Christian Becker at the University of Vienna. During this period, he worked on the semisynthesis of prion protein variants carrying glycan mimics and investigated their biophysical/biochemical properties in vitro. Currently, he is working as a postdoctoral researcher at the Leiden Institute of Chemistry (Netherlands), Bioorganic Synthesis Division under the guidance of Dr. Sander van Kasteren. His research interests are directed towards to the study kinetics of antigen processing & presentation using bioorthogonal chemistry as well as semisynthesis of posttranslationally modified antigens.

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