15529-90-5Relevant articles and documents
Diversity in Gold Finger Structure Elucidated by Traveling-Wave Ion Mobility Mass Spectrometry
Du, Zhifeng,de Paiva, Raphael E. F.,Nelson, Kristina,Farrell, Nicholas P.
, p. 4464 - 4467 (2017)
Traveling wave ion mobility (TWIM) mass spectrometry (MS) is a powerful method for the structural and conformational analysis of proteins and peptides, enabling the differentiation of isomeric peptides (or proteins) that have the same sequence but are modified at different residues. In this study, the TWIM-MS technique was used to separate isomeric AuI metallopeptide ions that were formed by ZnII displacement from the parent zinc fingers (ZFs). The synthetic gold finger peptides were derived from the C-terminus of the HIV nucleocapsid p7 protein (NCp7-F2) and finger 3 of the Sp1 transcription factor (Sp1-F3). TWIM-MS enabled the acquisition of distinct product ion spectra for each isomer, clearly indicating the binding sites for the major conformers in the presence of multiple coordination possibilities. Collision cross-section measurements showed that the aurated peptide has a slightly more compact structure than the parent zinc compound NCp7-F2, which showed only one conformation.
Gold-phosphine binding to de novo designed coiled coil peptides
Peacock, Anna F.A.,Bullen, Gemma A.,Gethings, Lee A.,Williams, Jonathan P.,Kriel, Frederik H.,Coates, Judy
, p. 298 - 305 (2012)
The coordination of the therapeutically interesting [AuCl(PEt3)] to the de novo designed peptide, TRIL23C, under aqueous conditions, is reported here. TRIL23C represents an ideal model to investigate the binding of [AuCl(PEt3)] to small proteins in an effort to develop novel gold(I) phosphine peptide adducts capable of mimicking biological recognition and targeting. This is due to the small size of TRIL23C (30 amino acids), yet stable secondary and tertiary fold, symmetric nature and the availability of only one thiol binding site. [AuCl(PEt3)] was found to react readily with the Cys side chain in a 1:1 ratio as confirmed by UV-visible, 31P NMR and mass spectrometry. Circular dichroism confirmed that the coiled coil structure was retained on coordination of the {Au(PEt3)}+ unit. Redesign of the exterior of TRIL23C based on a biologically relevant recognition sequence found in GCN4, did not alter the coordination chemistry of [AuCl(PEt3)]. To the best of our knowledge, this represents the first report on the coordination of gold(I) phosphine compounds to de novo designed peptides, and could lead to the generation of novel gold(I) phosphine peptide therapeutics in the future.
Probing the HIV-1 NCp7 Nucleocapsid Protein with Site-Specific Gold(I)-Phosphine Complexes
De Paiva, Raphael E. F.,Du, Zhifeng,Peterson, Erica J.,Corbi, Pedro P.,Farrell, Nicholas P.
, p. 12308 - 12318 (2017)
In this work, we examined a series of thiophilic Au(I) compounds based on [Au(L)(PR3)] (L = Cl-, 4-dimethylaminopyridine (dmap); R= ethyl (Et), cyclohexyl (Cy)) for chemoselective auration of the C-terminal HIV nucleocapsid protein NCp7 F2 and the full HIV NCp7 (NC, zinc finger (ZnF)) as probes of nucleocapsid topography. The choice of phosphine allowed electronic and steric effects to be considered. The use of the heterocycle leaving group allowed us to study the effect of possible π-stacking with the essential tryptophan residue of NC on the reactivity and selectivity, mimicking the naturally occurring interaction between the zinc finger and nucleic acids. We also examined for comparison the standard gold-phosphine compound auranofin, which contains an S-bound glucose coordinated to the {Au(PEt3)} moiety. Both the nature of the phosphine and the nature of L affect the reactivity with the C-terminal NCp7 F2 and the full NC. 31P NMR spectroscopy showed the formation of long-lived {Au(PR3)}-ZnF species in all cases, but in the case of NCp7 F2, a selective interaction in the presence of the dmap ligand was observed. In the case of auranofin, an unusual Au-His (rather than Au-Cys) coordination was indicated on NC. The overall results suggest that it is useful to consider three aspects of zinc finger structure in considering the profile of chemical reactivity: (i) the zinc-bound cysteines as primary nucleophiles; (ii) the zinc-bound histidine as a spectator ligand; and (iii) ancillary groups not bound to Zn but essential for ZnF function such as the essential tryptophan in NCp7 F2 and NC. Modification of fully functional NC zinc finger by the Cy3P-containing species confirmed the inhibition of the NC-SL2 DNA interaction, as evaluated by fluorescence polarization.
Synthesis and Structure-Activity Relationship Study of Antimicrobial Auranofin against ESKAPE Pathogens
Wu, Bin,Yang, Xiaojian,Yan, Mingdi
, p. 7751 - 7768 (2019/09/10)
Auranofin, an FDA-approved arthritis drug, has recently been repurposed as a potential antimicrobial agent; it performed well against many Gram-positive bacteria, including multidrug resistant strains. It is, however, inactive toward Gram-negative bacteria, for which we are in dire need of new therapies. In this work, 40 auranofin analogues were synthesized by varying the structures of the thiol and phosphine ligands, and their activities were tested against ESKAPE pathogens. The study identified compounds that exhibited bacterial inhibition (MIC) and killing (MBC) activities up to 65 folds higher than that of auranofin, making them effective against Gram-negative pathogens. Both thiol and the phosphine structures influence the activities of the analogues. The trimethylphosphine and triethylphosphine ligands gave the highest activities against Gram-negative and Gram-positive bacteria, respectively. Our SAR study revealed that the thiol ligand is also very important, the structure of which can modulate the activities of the AuI complexes for both Gram-negative and Gram-positive bacteria. Moreover, these analogues had mammalian cell toxicities either similar to or lower than that of auranofin.
