Targeting retroviral Zn finger-DNA interactions: a small-molecule approach using the electrophilic nature of trans-platinum-nucleobase compounds.
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.
Anzellotti
Atilio I
AI
Department of Chemistry, Virginia Commonwealth University, PO Box 842006, Richmond, Virginia 23284, USA.
Liu
Qin
Q
Bloemink
Marieke J
MJ
Scarsdale
J Neel
JN
Farrell
Nicholas
N
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
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