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

Socpus ID

84875214662 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84875214662

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