Title
Two-Component Covalent Inhibitor
Keywords
Aryl azide; Covalent inhibitors; DNA polymerase; Drug design; Enzymes; Irreversible inhibitors; Nucleotide analogs; Pyrene
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. © 2013 Elsevier Ltd. All rights reserved.
Publication Date
4-1-2013
Publication Title
Bioorganic and Medicinal Chemistry
Volume
21
Issue
7
Number of Pages
1988-1991
Document Type
Article
Personal Identifier
scopus
DOI Link
https://doi.org/10.1016/j.bmc.2013.01.021
Copyright Status
Unknown
Socpus ID
84875214662 (Scopus)
Source API URL
https://api.elsevier.com/content/abstract/scopus_id/84875214662
STARS Citation
Cornett, Evan M.; Gerasimova, Yulia V.; and Kolpashchikov, Dmitry M., "Two-Component Covalent Inhibitor" (2013). Scopus Export 2010-2014. 6818.
https://stars.library.ucf.edu/scopus2010/6818