Chemo- and Site-Selective Lysine Modification of Peptides and Proteins under Native Conditions Using the Water-Soluble Zolinium

Site-selective lysine modification of peptides and proteins
in
aqueous solutions or in living cells is still a big challenge today.
Here, we report a novel strategy to selectively quinolylate lysine
residues of peptides and proteins under native conditions without
any catalysts using our newly developed water-soluble zoliniums. The
zoliniums could site-selectively quinolylate K350 of bovine serum
albumin and inactivate SARS-CoV-2 3CLprovia covalently modifying two highly conserved lysine residues (K5 and
K61). In living HepG2 cells, it was demonstrated that the simple zoliniums
(5b and 5B) could quinolylate protein lysine
residues mainly in the nucleus, cytosol, and cytoplasm, while the
zolinium-fluorophore hybrid (8) showed specific lysosome-imaging
ability. The specific chemoselectivity of the zoliniums for lysine
was validated by a mixture of eight different amino acids, different
peptides bearing potential reactive residues, and quantum chemistry
calculations. This study offers a new way to design and develop lysine-targeted
covalent ligands for specific application.