Histidine-Covalent Stapled Alpha-Helical Peptides Targeting hMcl‑1

Several novel and effective cysteine targeting (Cys)
covalent drugs
are in clinical use. However, the target area containing a druggable
Cys residue is limited. Therefore, methods for creating covalent drugs
that target different residues are being looked for; examples of such
ligands include those that target the residues lysine (Lys) and tyrosine
(Tyr). Though the histidine (His) side chain is more frequently found
in protein binding locations and has higher desirable nucleophilicity,
surprisingly limited research has been done to specifically target
this residue, and there are not many examples of His-targeting ligands
that have been rationally designed. In the current work, we created
novel stapled peptides that are intended to target hMcl-1 His 252
covalently. We describe the in vitro (biochemical, NMR, and X-ray)
and cellular design and characterization of such agents. Our findings
further suggest that the use of electrophiles to specifically target
His residues is warranted.