ABSTRACT
The HIV nucleocapsid NCp7-SL2 RNA interaction is interrupted in the presence of a formally substitution-inert gold(dien)-nucleobase/N-heterocycle AuN4 compound where the N-heterocycle serves the dual purposes of a template for "non-covalent" molecular recognition of the essential tryptophan of the protein, mimicking the natural reaction and subsequent "fixation" by Au-Cys bond formation providing a chemotype for a new distinct class of nucleocapsid-nucleic acid antagonist.
Subject(s)
Organogold Compounds/chemistry , Organogold Compounds/pharmacology , RNA, Viral/antagonists & inhibitors , gag Gene Products, Human Immunodeficiency Virus/antagonists & inhibitors , Dose-Response Relationship, Drug , Molecular Structure , Structure-Activity RelationshipABSTRACT
The reaction of [Au(dien)(N-heterocycle)](3+) (AuN4) coordination compounds with simple amino acids and zinc finger proteins is reported. Compared to [AuCl(dien)](2+), NMR studies show that the presence of a more substitution-inert N-donor as the putative leaving group slows the reaction with the sulfur-containing amino acids N-acetylmethionine (NAcMet) and N-acetylcysteine (NAcCys). Lack of ligand dissociation upon reaction with NAcCys indicates, to our knowledge, the first long-lived N-heterocycle-Au-S species in solution. Reactions with zinc finger proteins show a higher reactivity with the Cys3His zinc finger than with Cys2His2, likely due to the presence of fewer aurophilic cysteines in the latter. Of the Au(III) compounds studied, [Au(dien)(DMAP)](3+) (DMAP = 4-dimethylaminopyridine) appears to be the least reactive, with ESI-MS studies showing the presence of intact zinc fingers at initial reaction times. These results, in combination with previously reported characterization and pH dependency studies, will further aid in optimizing the structure of these AuN4 species to obtain a substitution-reactive yet selective compound for targeting zinc finger proteins.
Subject(s)
Coordination Complexes/chemistry , Gold/chemistry , Heterocyclic Compounds/chemistry , Peptides/chemistry , Zinc Fingers , Zinc/chemistry , 4-Aminopyridine/analogs & derivatives , 4-Aminopyridine/chemistry , Acetylcysteine/chemistry , Animals , Cattle , Coordination Complexes/chemical synthesis , DNA/chemistry , Ethidium , Fluorescence , Heterocyclic Compounds/chemical synthesis , Ligands , Methionine/analogs & derivatives , Methionine/chemistry , Spectrometry, Fluorescence , Spectrometry, Mass, Electrospray IonizationABSTRACT
A survey of selected N-heterocycle ligands showed that platination of 4-N-dimethylaminopyridine (DMAP) in [Pt(dien)L](2+) (dien=diethylenetriamine) gave especially strong π-π stacking interactions with tryptophan and the tryptophan-containing C-terminal zinc finger (ZF) of the HIV (human immunodeficiency virus) nucleocapsid protein NCp7. The association constants (all at 10(3)M(-1)) were significantly stronger (25.0 and 28.1 for tryptophan and ZF respectively) than those previously measured for the purine nucleobase 9-ethylguanine (9EtG) in [Pt(dien)(9EtG)](2+) (6.88 and 7.55 for tryptophan and ZF respectively). Extension to Pd and Au complexes also confirmed the utility of DMAP in assisting stacking interactions. The results confirm the utility of a "bioinorganic" approach to targeting and inactivation of medicinal chemistry targets using the dual approach of target recognition (non-covalent) followed by target fixation (covalent).
Subject(s)
Coordination Complexes/chemistry , Gold/chemistry , Heterocyclic Compounds/chemistry , Palladium/chemistry , Platinum/chemistry , Tryptophan/chemistry , Amino Acid Sequence , Coordination Complexes/chemical synthesis , HIV/chemistry , HIV/genetics , Humans , Ligands , Magnetic Resonance Spectroscopy , Molecular Structure , Zinc Fingers/geneticsABSTRACT
Novel Au(III)(dien)(N-heterocycle) compounds, including the first Au(III)N3(N-purine) examples, are reported. The acidity of the dien ligand is affected by the nature of the fourth ligand as a leaving group. The metal center of [Au(dien)(N-heterocycle)](3+) compounds was shown to be more stable to reduction than when Cl(-) is present, with consequences for reactivity with biomolecules: specifically, significant enhancement of π-π-stacking interactions with tryptophan relative to isostructural and isoelectronic platinum(II) and palladium(II) compounds.
