Two-component covalent inhibitor

    Authors

    E. M. Cornett; Y. V. Gerasimova;D. M. Kolpashchikov

    Comments

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    Abbreviated Journal Title

    Bioorg. Med. Chem.

    Keywords

    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

    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 multicomponent systems. (C) 2013 Elsevier Ltd. All rights reserved.

    Journal Title

    Bioorganic & Medicinal Chemistry

    Volume

    21

    Issue/Number

    7

    Publication Date

    1-1-2013

    Document Type

    Article

    Language

    English

    First Page

    1988

    Last Page

    1991

    WOS Identifier

    WOS:000316770300040

    ISSN

    0968-0896

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