Au(<scp>iii</scp>) compounds as HIV nucleocapsid protein (NCp7)–nucleic acid antagonists

Spell, Sarah R.; Mangrum, John B.; Peterson, Erica J.; Fabris, Daniele; Ptak, Roger G.; Farrell, Nicholas

doi:10.1039/c6cc07970a

Cited by 30 publications

(45 citation statements)

References 55 publications

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“…These displacements have important biological consequences and potential therapeutic applications through the inhibition of the intrinsic nucleic acid interactions of the parent zinc fingers. [5] Theg old complex shows micromolar efficacyi ni nhibiting viral infectivity,consistent with the ability to alter the native structure. [3] Similar results have been obtained using poly(ADP-ribose) polymerase 1(PA RP-1;ADP = adenosine diphosphate).…”

mentioning

confidence: 71%

“…[13] Replacement of Zn 2+ in the full zinc finger NC eliminated the nucleic acid binding abilities of the peptide,w hich is crucial to its biological function in the HIV replication cycle. [5,14] For{ AuF} derived from Sp1-F3, only one conformation was observed (for its MS/MS spectrum, see Figure 4c). [5,14] For{ AuF} derived from Sp1-F3, only one conformation was observed (for its MS/MS spectrum, see Figure 4c).…”

Section: Zuschriftenmentioning

confidence: 99%

“…[2] Mass spectrometry has identified multiple {Au n F} (n = 1-3) species following Zn 2+ displacement in both the C-terminal finger of the HIV NCp7 nucleocapsid protein (NCp7-F2, F2) and finger 3ofthe Sp1 transcription factor (Sp1-F3, F3), af eature easily explained by the presence of multiple cysteine residues in the zinc finger template. [5] Thea uration of ZF peptides represents ap roblem of wide interest in bioinorganic chemistry as well as af undamental problem for inorganic chemistry as we are evaluating the replacement of at etrahedrally coordinated Zn II ion by al inearly coordinated Au I ion. [4] TheZ n 2+ ion in the "full" two-finger nucleocapsid (NC) protein is also displaced by Au III (from [Au(dien)(9-EtGuanine)] 3+ )p roducing {Au n F}.…”

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confidence: 99%

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Diversity in Gold Finger Structure Elucidated by Traveling‐Wave Ion Mobility Mass Spectrometry

Paiva

Nelson

et al. 2017

Angew Chem Int Ed

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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 Au metallopeptide ions that were formed by Zn 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.

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confidence: 71%

Section: Zuschriftenmentioning

confidence: 99%

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confidence: 99%

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Diversity in Gold Finger Structure Elucidated by Traveling‐Wave Ion Mobility Mass Spectrometry

Paiva

Nelson

et al. 2017

Angew Chem Int Ed

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“…[14,15] Theredox stability (see Figure S4). [16,17] In contrast, for 1 and NC we first observe,along with oxidized apopeptide,a{Au(bnpy)-F} species where the ligand remains bound to Au upon initial reaction with the peptide (Figure 2A). In contrast, for 1 the reduction process happens at À1.21 V. The À0.8 V difference indicates an increased stability of 1 towards reduction, av ery desirable property for ac ompound that will be exposed to the Cys-rich biological media.…”

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confidence: 94%

Gold‐Catalyzed C–S Aryl‐Group Transfer in Zinc Finger Proteins

Paiva

Nakahata

et al. 2018

Angewandte Chemie

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Reaction of the Au-C Nchelate [Au(bnpy)Cl 2 ]with the full-length zinc finger (ZnF;Z nCys 3 His) of HIV nucleocapsid protein NCp7 results in C-S aryl transfer from the Au III organometallic species to acysteine of the ZnF.The reaction is general and occurs even for finger 3ofthe transcription factor Sp1, containing aZ nCys 2 His 2 coordination sphere.T his reaction is the first demonstration of group transfer from ac oordination compound to biologically important zinc fingers,a nd is especially noteworthy for the ZnCys 2 His 2 transcription factors.T he work expands the corpus of organometallic species which can efficiently modify biomolecules through C-atom transfer.T he electronic features of the gold compound leading to this unexpected reaction were explored by X-raya bsorption spectroscopy.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

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“…A number of compounds in the literature are known to inhibit NCp7, [12,13] and these molecules typically have electrophilic groups that react with the most nucleophilic cysteine in NCp7 (shown to be Cys 49 ). These inhibitors are also generally toxic due to non-specific reactions with other cellular targets.…”

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confidence: 99%

Probing Mercaptobenzamides as HIV Inactivators via Nucleocapsid Protein 7

et al. 2017

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Human immunodeficiency virus type 1 (HIV-1) nucleocapsid protein 7 (NCp7), a zinc finger protein, plays critical roles in viral replication and maturation and represents an attractive target for drug development. However, development of drug-like molecules that inhibit NCp7 has been a significant challenge. In this report, a series of novel 2-mercaptobenzamide prodrugs have been investigated for anti-HIV activity in the context of NCp7 inactivation. The molecules are synthesized from the corresponding thiosalicylic acids, and they are all crystalline solids and stable at room temperature. Derivatives with a range of amide side chains and aromatic substituents were synthesized and screened for anti-HIV activity. Wide ranges of antiviral activity were observed, with IC50 values ranging from 1 to 100 μM depending on subtle changes to the substituents on the aromatic ring and the sidechain. Results from these structure-activity relationships were fit to a probable mode of intracellular activation and interaction with NCp7 to explain variations in antiviral activity. Our strategy to make a series of mercaptobenzamide prodrugs represents a general new direction to make libraries that can be screened for anti-HIV activity.

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Au(iii) compounds as HIV nucleocapsid protein (NCp7)–nucleic acid antagonists

Cited by 30 publications

References 55 publications

Diversity in Gold Finger Structure Elucidated by Traveling‐Wave Ion Mobility Mass Spectrometry

Diversity in Gold Finger Structure Elucidated by Traveling‐Wave Ion Mobility Mass Spectrometry

Gold‐Catalyzed C–S Aryl‐Group Transfer in Zinc Finger Proteins

Probing Mercaptobenzamides as HIV Inactivators via Nucleocapsid Protein 7

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