Over the past decade there has been a renaissance in the use of large polypeptides and proteins as therapeutic agents. This has led to significant demand for technologies to rapidly and efficiently access these biomolecules, especially those bearing tailor-made modifications to maximize specificity and activity, or to probe biological function (e.g. through incorporation of post-translational modifications, fluorophores and/or imaging reagents).¹ We have recently developed a number of synthetic and semi-synthetic technologies that enable efficient production of peptides and proteins with homogeneous post-translational modifications at pre-determined sites.^2,3 This talk will highlight: (1) the generation of proteins with site-specific and homogeneous post-translational modifications via new peptide ligation chemistries,^3-5 (2) rapid ligation-based assembly of libraries of modified proteins for performing “medicinal chemistry on proteins”⁶ and (3) the development of chemoselective and regioselective late-modification chemistry for the efficient generation of bioactive modified proteins.⁷

References

• Kulkarni et al. Nature Rev. Chem. 2018, 2, 0122.
• Kulkarni et al. Nature Protocols, 2019, 14, 2229.
• Chisholm et al. J. Am. Chem. Soc.2020, 142, 1090-1100.
• Premdjee et al. J. Am. Chem. Soc.2021, 143, 5336.
• Kulkarni et al. Angew. Chem. Int. Ed. 2022, 61, e202200163
• E. Watson et al. Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 13873.
• Dowman et al. Nature Commun. 2022, 6885