Inducible Alkylation of DNA by a Quinone Methide-peptide Nucleic Acid Conjugate

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2012 Jan 17

PMID 22243337

Citations 8

Authors

Yang Liu

Steven E Rokita

Affiliations

Soon will be listed here.

Abstract

The reversibility of alkylation by a quinone methide intermediate (QM) avoids the irreversible consumption that plagues most reagents based on covalent chemistry and allows for site specific reaction that is controlled by the thermodynamics rather than kinetics of target association. This characteristic was originally examined with an oligonucleotide QM conjugate, but broad application depends on alternative derivatives that are compatible with a cellular environment. Now, a peptide nucleic acid (PNA) derivative has been constructed and shown to exhibit an equivalent ability to delivery the reactive QM in a controlled manner. This new conjugate demonstrates high selectivity for a complementary sequence of DNA even when challenged with an alternative sequence containing a single T/T mismatch. Alternatively, alkylation of noncomplementary sequences is only possible when a template strand is present to colocalize the conjugate and its target. For efficient alkylation in this example, a single-stranded region of the target is required adjacent to the QM conjugate. Most importantly, the intrastrand self-adducts formed between the PNA and its attached QM remained active and reversible over more than 8 days in aqueous solution prior to reaction with a chosen target added subsequently.

Citing Articles

Directing Quinone Methide-Dependent Alkylation and Cross-Linking of Nucleic Acids with Quaternary Amines.

Hutchinson M, Deeyaa B, Byrne S, Williams S, Rokita S Bioconjug Chem. 2020; 31(5):1486-1496.

PMID: 32298588 PMC: 7242154. DOI: 10.1021/acs.bioconjchem.0c00166.

Synthesis and Improved Cross-Linking Properties of C5-Modified Furan Bearing PNAs.

Elskens J, Manicardi A, Costi V, Madder A, Corradini R Molecules. 2017; 22(11).

PMID: 29156637 PMC: 6150320. DOI: 10.3390/molecules22112010.

Targeting duplex DNA with the reversible reactivity of quinone methides.

Huang C, Liu Y, Rokita S Signal Transduct Target Ther. 2017; 1.

PMID: 28458944 PMC: 5407369. DOI: 10.1038/sigtrans.2016.9.

Efforts toward treatments against aging of organophosphorus-inhibited acetylcholinesterase.

Zhuang Q, Young A, Callam C, McElroy C, Ekici O, Yoder R Ann N Y Acad Sci. 2016; 1374(1):94-104.

PMID: 27327269 PMC: 4940266. DOI: 10.1111/nyas.13124.

Crosslinking reactions of 4-amino-6-oxo-2-vinylpyrimidine with guanine derivatives and structural analysis of the adducts.

Kusano S, Ishiyama S, Lam S, Mashima T, Katahira M, Miyamoto K Nucleic Acids Res. 2015; 43(16):7717-30.

PMID: 26245348 PMC: 4652779. DOI: 10.1093/nar/gkv797.

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