Enhancement of the physicochemical properties of [Pt(dien)(nucleobase)]²⁺ for HIVNCp7 targeting

Abstract

Building from tryptophan to the tryptophan-containing HIV Nucleocapsid 7 (HIVNCp7) protein we combine biophysical and computational studies to enhance stacking interactions of purines through platination. The incorporation into a weak Lewis acid electrophile, [Pt(dien)(Nucleobase)]2+ may lead to disruption of the HIVNCp7-RNA interaction.

Investigation of 1-Methylcytosine as a Ligand in Gold(III) Complexes: Synthesis and Protein Interactions

“…Compared to the Pt(II) and Pd(II) analogs, the Au(III) complexes show a higher affinity for NAcTrp, consistent with the previous literature [5,20]. The lower affinity of B for NAcTrp than the DMAP analog and similar affinity compared to the 9-EtGua analog is surprising given the intermediate basicity of 1-MeCyt.…”

“…This interaction is in contrast to the interactions observed in the Pt(II) analogs, in which reduction and incorporation of the Pt(II) metal center is not seen. Instead, the metal center is observed with the ligands intact and with the zinc still incorporated [3,5,20]. Like previously reported aurated DMAP and 9-EtGua analogs, but unlike the platinated analogs, peaks representing the unreacted zinc-finger protein are not seen at the initial time point, highlighting the increased reactivity of the Au(III) metal center.…”

Covalent versus Noncovalent Binding of Ruthenium η6‐p‐Cymene Complexes to Zinc‐Finger Protein NCp7

“…In addition to covalent binding by coordination substitution, Ru‐complexes can also bind to protein through noncovalent binding, in which π‐π stacking plays an important role . It has been reported that metal complexes, such as [Au(dien)(9‐EtGua)] 3+ and [Pt(dien)(nucleobase)] 2+ , bind to NCp7 through π‐π stacking with the tryptophan residue . In addition, the noncovalent interaction could also promote covalent binding of metal complexes to proteins .…”

Bioinorganic applications of gold and platinum coordination compounds: a brief historical overview and recent advances in 2017

“…[20] Yellow board: platinum(II) compound (40) designed by Zhu and co-authors [21] as probes for lipopolysaccharide endotoxin and discrimination between Gram-negative and Grampositive bacterial strains. Blue board: platinum(II) compounds (41-52) designed by Tsotsoros and co-authors [22] containing the general motif [Pt(chelate)(N-donor)] 2+ and evaluated as anti-HIV agents. Purple board: Peterson and co-authors [23] demonstrated that the polynuclear platinum compounds triplatin (53) and triplatin NC (54) can bind to glycans.…”

“…Tsotsoros, Farrell and co-authors presented to the scientific community a systematic strategy to understand the interaction between platinum-nucleobase compounds and the tryptophan-containing HIV NCp7. [22] The inherent π-π stacking properties of the compound [Pt(chelate) (N-donor)] 2+ were modulated by systematic variation of the tridentate ligand (diethylenetriamine and Me-substituted derivatives) and N-donor (nucleobase or nucleoside), leading to compounds 41-52. The activity of [Pt(dien)(9-EtGua)] 2+ (41) against HIV-1 strains BaL, NL4-3 and 91-US001 in peripheral mononuclear blood (PBMC) cells showed only modest HIV inhibitory activity for the latter with an IC 50 = 28.61 mM.…”