title: Selective inhibition of engineered receptors via proximity-accelerated alkylation.
abstract: A new approach for creating allele-specific inhibitors is demonstrated. In this approach, a receptor and ligand are engineered to contain complementary reactive groups that form a covalent bond via a proximity-accelerated reaction upon formation of the receptor-ligand complex, irreversibly modulating the biological function of the receptor. This approach is demonstrated in the cyclophilin-cyclosporin receptor-ligand system by introducing thiol and acrylamide functional groups in the receptor and ligand, respectively.
authors.affiliation: Departments of Chemistry and Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Levitsky
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ciolli
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Belshaw
mesh_terms: D000478:Alkylation; D000483:Alleles; D001665:Binding Sites; D021984:Cyclophilin A / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D016572:Cyclosporine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D016297:Mutagenesis, Site-Directed; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C028752:cyclosporin receptor; D016572:Cyclosporine; D021984:Cyclophilin A; D019696:Peptidylprolyl Isomerase