9z3v
Histidine-covalent 165G1 targeting hMcl-1
Structural highlights
FunctionMCL1_HUMAN Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.[1] Publication Abstract from PubMedThe design of irreversible drugs has resulted, over the past decade, in several new therapeutics in oncology that present improved pharmacodynamic and pharmacoK(I)netic properties compared to reversible ligands. Nevertheless, most ligands to date are designed to target a cysteine (Cys) residue, which is not a very common amino acid and only rarely occurs in protein target binding sites, thereby limiting the applicability of this covalent targeting approach. Recent work from our laboratory and others suggests that, after Cys, histidine (His) residues can be particularly suitable for covalent substitution with proper electrophiles. Using a ligand-first, structure-based approach, we assessed the possibility of using different electrophiles including acrylamides, chloroacetamides, or aryl fluorosulfates to target His residues covalently. Targeting His224 of hMcl-1 with model peptides, we demonstrate that both aryl fluorosulfates and chloroacetamides can be used to target His residues efficiently. Our studies also report strategies and biophysical approaches useful for the design and characterization of such His-covalent agents. Covalent Targeting of Histidine Residues: A Ligand-First Approach.,Alboreggia G, Atienza EL, Muzzarelli K, Assar Z, Pellecchia M J Med Chem. 2026 Apr 29. doi: 10.1021/acs.jmedchem.5c03255. PMID:42054250[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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