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ATP‐DNA conjugates as potential helicase inhibitors
Author(s) -
Harrison Melody K.,
Warthen Chris R.,
Cameron Craig E.,
Raney Kevin D.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb51-d
Subject(s) - helicase , nucleic acid , biochemistry , dna , ns3 , oligonucleotide , biology , enzyme , chemistry , rna , gene , protease
Helicases are enzymes that manipulate nucleic acids during replication, recombination, transcription, and translation. They are ubiquitous enzymes found in all organisms and many viruses. As such, helicases are potential targets for therapeutic purposes. Hepatitis C virus (HCV) NS3 protein contains the helicase domain that is essential for viral replication. The helicase activity of NS3, like all helicases, is dependent both on binding of nucleic acid and hydrolysis of ATP. The crystal structure of several different helicases reveals a relatively open channel between the nucleic acid and ATP binding sites. Therefore, it might be possible to design a molecule that will simultaneously bind both sites and thereby increase binding affinity over that of ATP or nucleic acid alone. A bi‐substrate conjugate was constructed in which an ATP analog and a short nucleic acid were covalently linked to opposite ends of a spacer arm of appropriate length. The conjugate was tested for binding to NS3 helicase and Dda helicase. Results indicate modest improvement in binding of the conjugate to Dda, but not NS3, when compared to the oligonucleotide. This work was supported by NIH grant AI060563 (K.D.R. and C.E.C.) and by NIH COBRE grant P20 RR15569 (University of Arkansas).