title: Targeting retroviral Zn finger-DNA interactions: a small-molecule approach using the electrophilic nature of trans-platinum-nucleobase compounds.
abstract: Noncovalent interactions are ubiquitous in ternary systems involving metal ions, DNA/RNA, and proteins and represent a structural motif for design of selective inhibitors of biological function. This contribution shows that small molecules containing platinated purine nucleobases mimic the natural DNA(RNA)-tryptophan recognition interaction of zinc finger peptides, specifically the C-terminal finger of HIV NCp7 protein. Interaction with platinum results in Zn ejection from the peptide accompanied by loss of tertiary structure. Targeting the NCp7-DNA interaction for drug design represents a conceptual advance over electrophiles designed for chemical attack on the zinc finger alone. These results demonstrate examples of a new platinum structural class targeting specific biological processes, distinct from the bifunctional DNA-DNA binding of cytotoxic agents like cisplatin. The results confirm the validity of a chemical biological approach for metallodrug design for selective ternary DNA(RNA)-protein interactions.
authors.affiliation: Department of Chemistry, Virginia Commonwealth University, PO Box 842006, Richmond, Virginia 23284, USA.
authors.forename: Atilio I
authors.initials: AI
authors.lastname: Anzellotti
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Marieke J
authors.initials: MJ
authors.lastname: Bloemink
authors.forename: J Neel
authors.initials: JN
authors.lastname: Scarsdale
authors.forename: Nicholas
authors.initials: N
authors.lastname: Farrell
mesh_terms: D000595:Amino Acid Sequence; D036022:Capsid Proteins / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D015195:Drug Design; D015683:Gene Products, gag / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010984:Platinum / Q000378:metabolism; D011485:Protein Binding; D013050:Spectrometry, Fluorescence; D021241:Spectrometry, Mass, Electrospray Ionization; D014764:Viral Proteins / Q000378:metabolism; D016335:Zinc Fingers; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D036022:Capsid Proteins; D015683:Gene Products, gag; C071884:NCP7 protein, Human immunodeficiency virus 1; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; D010984:Platinum; D004247:DNA