title: Two-component covalent inhibitor.
abstract: 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 multi-component systems.
authors: Chemistry Department, University of Central Florida, 4000 Central Florida Blvd, Orlando, FL 32816, USA.
authors: Evan M
authors: EM
authors: Cornett
authors: Yulia V
authors: YV
authors: Gerasimova
authors: Dmitry M
authors: DM
authors: Kolpashchikov
mesh_terms: D017122:Bacteriophage T4 / Q000737:chemistry / Q000201:enzymology*; D001665:Binding Sites; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D008027:Light; D019384:Nucleic Acid Synthesis Inhibitors; D011485:Protein Binding; D013942:Thymine Nucleotides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D013942:Thymine Nucleotides; D004259:DNA-Directed DNA Polymerase; C024157:thymidine 5'-triphosphate