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.

Zinc finger proteins as templates for metal ion exchange: Substitution effects on the C-finger of HIV nucleocapsid NCp7 using M(chelate) species (M = Pt, Pd, Au)

“…Secondary structure characterization of the zinc finger (ZF) was monitored using ESI-MS and CD spectroscopy. The data obtained were in agreement with reported values in the literature [5]. All zinc finger samples were prepared in an aqueous solvent at 1.17 mM and incubated immediately with the appropriate concentration of metal complex, also in water.…”

“…The CD (circular dichroism) spectrum of the zinc finger studied here is characterized by a broad band with a slight positive maximum centered at 210 nm and a stronger band with negative ellipticity centered at 190-200 nm. In the absence of zinc, there is a significant increase in the intensity of the negative band as well as a slight red shift, indicative of a random coil [5]. The positive band also suffers a decrease in intensity.…”

“…Recently we have shown that platinum complexes such as trans-[PtCl(9-EtGH)(py) 2 ] + may bind to the C-terminal finger of the HIV nucleocapsid protein NCp7 with eventual dislocation of Zn, incorporation of Pt(II) into the binding site and concomitant loss of protein conformation [5]. Such chemistry may be implicated in the antiviral activity of this class of compounds [6].…”

Identification of [PtCl2(phen)] Binding Modes in Amyloid‐β Peptide and the Mechanism of Aggregation Inhibition

“…Similar substitution has been observed for platinum-induced zinc ejection from zinc-finger proteins. [19] This observation suggests that Pt II coordination to Ab is stronger than that of Cu II or Zn II . Therefore, the binding of platinum to the histidine residues, which are also the binding sites of Cu 2 + and Zn 2 + , is one of the key factors in the inhibition of Ab aggregation.…”

Interaction identification of Zif268 and TATAZF proteins with GC‐/AT‐rich DNA sequence: A theoretical study

“…[20][21][22][23][24][25][26] Farrell and coworkers have applied the zinc finger model to biomimetic studies of protein/Pt/DNA interactions. [27][28][29] Furthermore, Greidman and Pabo successfully used the three-zinc-finger domain derived from Zif268 as a framework and achieved further success in selecting the TATA ZF protein by the sequential selection strategy. 19,30 The TATA ZF protein binding to the TATA box indicates that the DNA binding affinity of the zinc finger peptides for AT-rich sequence is estimated at less than nanomolar order.…”