Two-component covalent inhibitor
Abbreviated Journal Title
Bioorg. Med. Chem.
Covalent inhibitors; Irreversible inhibitors; Drug design; DNA; polymerase; Enzymes; Nucleotide analogs; Aryl azide; Pyrene; DNA-POLYMERASES; SENSITIZED PHOTOMODIFICATION; BINARY-SYSTEM; DRUG; DESIGN; REPLICATION; AFFINITIES; COMPLEXES; PROTEINS; LINKING; TARGETS; Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, ; Organic
Inhibitors that covalently damage proteins or nucleic acids offer great potency, but are difficult to rationally design and suffer from poor specificity. Here we outline a general concept for constructing covalent inhibitors, called the two-component covalent inhibitor (TCCI). The approach takes advantage of two ligand analogs equipped with pre-reactive groups. Binding of the analogs to the adjacent sites of a target biopolymer brings the pre-reactive groups in close proximity and causes their interaction followed by covalent damage of the target. In the present study we used light-activated pre-reactive groups to inactivate a DNA polymerase. It was found that the efficiency of a traditional single-component inhibitor was greatly reduced in the presence of a non-target protein, while the TCCI was not significantly affected. Our findings suggest that TCCI approach has advantages in inactivation of biopolymers in complex multicomponent systems. (C) 2013 Elsevier Ltd. All rights reserved.
Bioorganic & Medicinal Chemistry
"Two-component covalent inhibitor" (2013). Faculty Bibliography 2010s. 3833.