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

Article abstract of DOI:10.1002/anie.201803082

Reaction of the Au–C N chelate [Au(bnpy)Cl₂] with the full-length zinc finger (ZnF; ZnCys₃His) of HIV nucleocapsid protein NCp7 results in C–S aryl transfer from the Au^III organometallic species to a cysteine of the ZnF. T

Full text of DOI:10.1002/anie.201803082

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Accepted Article
Title: Au-catalyzed C-S aryl group transfer in Zinc Finger Proteins
Authors: Raphael Enoque, Zhifeng Du, Douglas Nakahata, Frederico
Lima, Pedro Corbi, and Nicholas P. Farrell
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803082
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10.1002/anie.201803082
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Au-catalyzed C-S aryl group transfer in Zinc Finger Proteins
Raphael E. F. de Paiva, Zhifeng Du, Douglas H. Nakahata, Frederico A. Lima, Pedro P. Corbi and
Nicholas P. Farrell*
Abstract: Reaction of the Au-C^N chelate [Au(bnpy)Cl2] with the full-
length Zinc Finger (ZnF, ZnCys3His) HIV Nucleocapsid protein NCp7
results in C-S bond transfer from the Au(III)-organometallic to a
cysteine of the ZnF. The reaction is general and occurs even for the
finger 3 of the transcription factor Sp1, containing a ZnCys2His2
coordination sphere. This is the first demonstration of group transfer
from a coordination compound to biologically important zinc fingers
and is especially noteworthy for the ZnCys2His2 transcription factors.
The work expands the corpus of organometallic species which can
The structures of the Au(III) compounds and zinc fingers
studied are shown in Figure 1. The organometallic compound 1
was compared to the bipyridine (bipy) and phenanthroline
(phen)-based compounds 2-4. Crystallographic data for the new
-
structure of 2 as its PF6 salt are given in Figure S1 and Table
S1. The crystal structures of 1-4 were compared with those
previously published (Table S2).[11–13] Full spectroscopic
characterization is provided for 1 (Figures S2, S3 and Table S3).
The 13C NMR spectrum confirms the Au-bound C at δ = -156
ppm as the most deshielded C atom in the molecule and thus
most susceptible to nucleophilic attack (Figure S2B and Table
efficiently modify biomolecules through
C atom transfer. The
electronic features of the Au compound leading to this unexpected
reaction were explored by X-ray Absorption Spectroscopy.
In this paper we report the unprecedented transfer of a C-
based ligand from an organometallic Au(III) compound to a
nucleophilic cysteine of the HIV NCp7 zinc finger nucleocapsid
protein. Zinc fingers (ZnFs) belong to the “structural” class of
zinc proteins, with four tightly bound ligands, usually using a
combination of cysteine and histidine donors. Whereas the
central zinc ion is redox inactive, structural zinc sites in general
enter into reversible and irreversible oxidation reactions through
the highly reactive zinc-bound cysteinates.[1,2] Protein
methylation is of great importance in a plethora of cellular
processes but ZnF methylation specifically is relatively rare.[3,4]
Probably one of the best known examples is the transfer of a
methyl group to one unique Zn-Cys ligand in the E. coli ADA
protein, which affects DNA damage repair.[5,6] Enteropathogenic
E. coli NleE uses an S-adenosyl-L-methionine-dependent
methyltransferase to specifically modify a ZnF cysteine in human
host TAB2/3 proteins, ubiquitin-chain sensory proteins involved
in NF-kB signaling.[7,8] In both these cases the modified
cysteines come from ZnCys4 cores whereas the histone
demethylase JMJD2A utilizes the ZnCys3His coordination
sphere.[9] We now report that C-atom transfer can be observed
from the Au-C bond in [Au(2-benzylpyridine)Cl2] ([Au(bnpy)]Cl2,
compound 1) to a Zn-Cys of the HIV nucleocapsid NCp7 (NC)
as well as the single C-terminal finger (ZnF2), a remarkable
demonstration of the unique chemistry inherent in these proteins.
The reaction is not restricted to the Cys3His (Cy2HisCys)
coordination sphere, being also observed in Finger 3 of the Sp1
human transcription factor, the first example of an
alkyl(aryl)ation on this ZnCys2His2 site. ZFs are excellent
templates for metal ion replacement reactions,[10] but this is the
first example where an originally metal-bound ligand is
transferred to the protein.
S3).
With respect to the electronic properties of the
organometallic, the “stabilization” of Au(III) using C^N chelates
has been used in drug design.[14,15] The redox stability of 1 was
compared to
2 and the precursor H[AuCl4] (Figure S4).
Reduction of 2 is observed at -0.42 V, compared to -0.45 V
[AuCl4]- (versus Ag/AgCl). On the other hand, for 1 the reduction
process happens at -1.21 V. The -0.8 V difference indicates an
increased stability of compound 1 towards reduction, a very
desirable property for a compound that will be exposed to the
Cys-rich biological media.Paragraph.
Figure 1. Au(III) compounds evaluated in this work. The organometallic
[Au(bnpy)Cl2] (1) was compared to [Au(bpy)Cl2]+ (2), [Au(4,4’-Me2bpy)Cl2]+ (3)
and [Au(phen)Cl2]+ (4). The zinc finger targets evaluated were the full-length
HIV-1 nucleocapsid protein NCp7 (NC) and the C-terminal finger (ZnF2 boxed),
and the third ZnF (F3) of the human transcription factor Sp1.
ESI-MS spectra show that the reaction of [Au(bpy)Cl2)]+ (2)
with the full-length NCp7 occurs with Zn replacement producing
{AunF} gold fingers, where all the ligands are lost and there is
probable reduction to Au(I), Figure S5. These results are
consistent with previous work using [Au(9-EtGua)(dien)]3+ and
[AuCl(dien)]2+ as well as for the reaction of 4 with a Cys3His
Raphael E. F. de Paiva, Zhifeng Du and Nicholas P. Farrell
Department of Chemistry, Virginia Commonwealth University, 1001 W.
Main Street, Richmond, Virginia 23284-2006, United States
E-mail: npfarrell@vcu.edu
model of the PARP-1 ZnF.[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 the Au upon initial
reaction with the peptide, Figure 2A. Over time, signals
corresponding to loss of the C-bound ligand and formation of
AunF appear, but most importantly a signal emerges whose m/z
and isotopic distribution corresponds to a {(bnpy)-oxiF} species
where the Au-bound ligand is transferred to the peptide through
C-S bond formation with concomitant loss of the Au atom, Figure
2 (B and C) and Figure S6.
Raphael E. F. de Paiva, Douglas H. Nakahata, Pedro P. Corbi
Institute of Chemistry, University of Campinas – UNICAMP, P.O. Box
6154, CEP 13083-970, Campinas, São Paulo, Brazil
Frederico Alves Lima
Centro Nacional de Pesquisa em Energia e Materiais, Brazilian
Synchrotron Light Laboratory – LNLS, CP 6192, 13084-971 Campinas,
SP, Brazil.
European XFEL GmbH, Holzkoppel 4, 22869 Schenefeld, Germany
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10.1002/anie.201803082
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Figure 2. A. Representative mass spectra for 1 with NC immediately upon reaction. B. Expansion of the 10+ ion state showing the signal assigned to the S-
arylated peptide species {(bnpy)-oxiF}10+ observed after 48h. C. Experimental and theoretical isotopic distributions of the {(bnpy)-oxiF}10+ species.
The C-S bond transfer also occurs for the C-terminal ZnF2,
(Figure 3 A and B). In this case, early time points show a
number of species containing both the {Au(bnpy)} and Zn ions.
Along with the emergence of the C-S {(bnpy)-oxiF} transfer
product, a species corresponding to {(Au(bnpy))3-F}3+ also
appears over time implying simultaneous auration of all three
cysteines of the peptide by the {Au(bnpy)} moiety (Figure 3B and
Figure S7). This latter observation confirms the conceptual utility
of Au complexes as thiophilic probes of ZnF structure.[18] For 2-4
and the C-terminal ZnF2, only AunF species are observed
(Figures S8-S10). All previously reported cysteine methylation in
zinc finger biology has occurred in ZnCys4 and ZnCys3His
coordination spheres.[5–9] Remarkably, the Au-mediated C-S
bond transfer occurs even in the case of the ZnCys2His2 sphere
of the Sp1 (ZnF3) transcription factor (Figure S11). The signal
appears to be present at the earliest time point and the isotopic
distribution is consistent with assignment (Figure S11B). To our
knowledge this is the first example of a cysteine alkyl(aryl)ation
on a transcription factor. Again, Compounds 2-4 with Sp1 ZnF3
show mostly oxidized peptide and some AuF species, Figure
S12.
1040.0417
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
A
Au(LLL)(bnpy)-ZnF4+
663.4858
1195.5278
1195.0265
1196.0284
1196.5289
1197.0293
Au(LLL)(bnpy)-Zn2F4+
1197.5297
[Au(LLL)(bnpy)]3-F3+
678.9659
m/z
Theoretical
1105.3609
Au(LLL)(bnpy)-F4+
1004.6983
647.5019
685.4299
605.3972
610.5719
1049.0446
1058.0489
1061.6809
1033.3371
638.6032
631.4852
657.5007
705.2541
694.6957
1023.3309
1013.9960
671.4796
725.5266
720.4864
621.5011
1079.0219
bnpy-oxiF2+
737.5854
740
1095.7295
1161.0501
1144.3408
1131.1462
1110.6900
1067.6785
1195.5266
1151.3600
1172.7931
0
0
620
640
660
680
700
720
1000
1020
1040
1060
1080
1100
m/z
1120
1140
1160
1180
1200
m/z
Figure 3. A. Mass spectra for 1 with NCp7 ZnF2 immediately upon reaction. B. The emergence of the signals corresponding to {(bnpy)-oxiF} is observed after 48
hours.
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To study the possible mechanisms and selectivity of the C-S
transfer we studied the reactions of 1 with the model S-donor N-
Acetyl-L-cysteine (nac) and with glutathione (gSH). For nac,
ESI-MS showed the immediate formation of both {Au(bnpy)-nac}
and {(bnpy)-nac} species, Figure 4A. NMR spectroscopy shows
the time-dependent nature of the reaction, which is easily
monitored by the change in the 1HNMR chemical shift of the
bridging CH2 protons of the ligand (which are inequivalent
because of the rigidity induced upon coordination, Figure 4B.
Two new signals appear in the δ(NH) region of nac, attributed to
first formation of the Au-S bond followed by the C-S transfer.
The rise of this latter peak, as well as the complex pattern of the
aromatic ligand, coincides with appearance of the CH2 singlet
and the transfer to the S atom. In contrast, ESI-MS spectra for 1
and gSH show the immediate formation of {Au(bnpy)-gSH},
some oxidized gSSg and no C-S transfer could be seen over
time (Figure S13). NMR spectra, monitored up to 24h, also
showed no evidence for the C-S transfer as evidenced by the
lack of appearance of the singlet -CH2 protons (Figure S14).
Specificity and efficiency in Au-ligand binding and
subsequent C-S transfer may be modulated both by the nature
of the Au compound and the nucleophilicity and accessibility of
the cysteines in the zinc finger core.[1,19–21] With respect to the
latter point it is noteworthy that the nucleocapsid ZnF cores
studied here have both highly nucleophilic and accessible
cysteines.[1,19–21] Some electronic features of the transfer
reaction have been further investigated by gold L3-edge X-ray
Absorption Spectroscopy (XAS), Figure 5.
.
Figure 5. XAS spectra of compounds 1 and 3, in comparison to the reaction
products 1 + the C-terminal ZnF2 of NCp7 and 1+nac. The significantly
reduced white line for
1 + ZnF2 is suggestive of a mixed Au(III)/Au(I)
environment through strong electron transfer into the Au center.[22]
XAS is sensitive to both the oxidation state of the metal
center and the nature of the coordinated ligands.[23] The
immediate freezing of samples can produce a snapshot of the
earliest time point, allowing the identification of the early steps of
the reaction and inference of the nature of the products. Au(III)
compounds show a strong white line peak as a consequence of
empty metal-centered d-orbitals promoting the allowed 2p3/2 
5d transitions in the L3 edge. The intensity of this peak can be
used as a fingerprint of the d-electron count, Table S4.
Compared to 3 and to [AuCl(dien)]2+,[22] the C^N-coordinated
ligand in 1 leads to a weaker white line signal, indicating a better
electron donor than the N^N and N^N^N counterparts. The
product of 1 with nac showed a slight increase in white line
intensity as a consequence of the stronger donating properties
of the thiolate when compared to chloride. A more significant
decrease in intensity is observed for 1+NCp7 (ZnF2), suggestive
of a significant electron density transfer into the Au center and
thus a more reduced gold or a mixed Au(III)/Au(I) population.[22]
The spectrum is very similar to that observed for [AuCl(dien)]2+
and ZnF2; from TD-DFT calculations on this system, binding of
two Cys or a Cys and His is likely.[22] Further, the experimental
Au L3-edge XAS spectrum resembles, but is not identical to, that
simulated for the theoretical models Cys-Au(I)-Cys or Cys-Au(I)-
His.[22] These features support the hypothesis that a reductive
elimination step facilitated by electron transfer from Cys to the
Au center facilitates the bond transfer, as in the early stages of
the overall reaction the C^N ligand is still bound.
Figure 4. A. MS spectrum obtained for the interaction between compound 1
[Au(bnpy)Cl2] and nac 24h after mixture in CH3CN. B. The same reaction was
followed over time by 1H NMR spectroscopy in DMSO-d6. (1) Free compound
1; (2) spectrum obtained immediately upon incubation of 1+nac, (3-5) spectra
obtained after 4, 24 and 96 h respectively; (6) free nac.
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Mononuclear reductive elimination has a strict demand for
cis positioning in the coordination sphere for the two species that
will undergo coupling.[24] In general (and perhaps surprisingly),
monofunctional substitution in Au(C^N) chelates occurs trans to
the Au-N rather than the Au-C bond.[25,26,27] This has been
confirmed by X-Ray crystallography for the reaction of 1 with
1,3,5-triazaphosphaadamantane (PTA).[25] In our system, this
places the S-donor cis to the benzyl moiety of the
cyclometalated ligand. Methylation studies (using methionine,
methylated cysteine) on a series of ZnF variants showed
significantly reduced binding to Co(II) and Zn(II) in comparison
to cysteinate.[28] Combined with our observations to date a
proposed pathway is shown in Scheme 1. Further studies are in
progress to delineate the detailed mechanism of reaction.
observation of multiple cysteine auration (Fig. 3B) emphasizes
this analogy. This inherent chemistry of zinc fingers is thus
extended for the first time to organometallic species
–
suggesting possible pathways to novel inhibition of the HIV
nucleocapsid target. The potential for multiple, step-wise
modification of cysteines in these multi-cysteine proteins is thus
a distinct advantage in this application. 1 inhibits the interaction
of NC with a SL2-DNA (stem loop 2) sequence and is more
effective than 2 (Figure S15), but is not as effective as the
previously studied [Au(dien)(L)]3+ (L = dmap, 9-EtGuanine).[16]
Whether this effect can be enhanced over time as C-S transfer
takes place is under investigation – the current results reflect
early time points of the 1-NC reaction.
In conclusion, the results have significance and biological
relevance in expanding the known chemistry of zinc finger
proteins, especially relevant for the ZnCys2His2 coordination
spheres of transcription factors, as well as for nucleocapsid
targeting and possibly unique mechanisms of detoxification of
metal-alkyl species. The work expands the corpus of
organometallic
species which can efficiently modify
biomolecules through C atom transfer. The generality and
intimate mechanism of these reactions is under further study as
well as further optimization approaches achieved by suitable
chemical design of the organometallic precursor.
Scheme 1. Generalized representation of an S-arylation reaction between
[Au(bnpy)Cl2] and a Cys-containing zinc finger. X is a ligand (most likely N-
donor) from peptide.
Modification of small molecules by transition-metal reagents is
a staple of organic synthesis but there are few examples of
organometallic-based modification of biomolecules.[29] Pd(II)
Acknowledgements
complexes
can be
used
for
cysteine conjugation
(bioconjugation) reactions through aryl group transfer and may
find application in production of stapled peptides and antibody-
drug conjugates.[30] The work reported here extends some of
these observations to Au-based organometallics. The potential
for cysteine modification by Au-C compounds from a previously
published report suggested poor efficiency and selectivity for 1,
where the proof-of-principle was the one available cysteine on
Human Serum Albumin (HSA).[31] This observation is further
borne out in our studies noting the difference between nac and
gSH. The additional presence of multiple cysteines in ZnFs also
This work was supported by a National Science Foundation
(NSF) grant CHE-1413189; Brazilian Council of Technological
and Scientific Development (CNPq) grant 442123/2014-0 and
scholarship 140466/2014-2; São Paulo State Research Council
(FAPESP) grant 2015/25114-4 and scholarship 2015/20882-3;
and by Brazilian Coordination Agency for the Improvement of
High-Level Personnel (CAPES), PVES grant 0580/2013. The
authors thank Bruno Morandi Pires for the help setting up the
electrochemical experiments and Erica Peterson for setting up
the NCp7/SL2 inhibition experiments.
allows for some apparent chemoselectivity - the reaction of
1
and the PARP-1 model ZnF showed formation of {Au(bnpy)-F}
species but no C-S transfer was observed.[32] Comparing nac to
gSH and NCp7 to PARP-1, it becomes clear that the Cys
microenvironment also plays a role. Thus the mere binding of
the organometallic to a Cys-containing biomolecule does not
suggest automatically that C-S transfer will occur.
The group atom transfer observed on ZnF proteins is formally
analogous to other Au-mediated C-R bond formation reactions,
where the R group is transferred from a Au-R moiety, such as
the formation of phosphonium salts from phosphines.[33] Au(III)
intermediates generated after oxidative addition of aryl-X to
Au(I)-phosphine compounds are also widely used for aryl
transfer and C-C coupling,[34] while Au(I)-catalyzed oxidative
allene-thiol coupling leads to the formation of vinyl sulfide
alcohols.[35] The observation of C-S transfer on a protein site is
analogous with early work on covalently binding NCp7 inhibitors
based on thioesters which oxidize Zn-Cys and modify the
peptide backbone by sequential Cys oxidation and/or acyl
transfer to the lysine of the zinc finger from thioesters.[36,37] The
Keywords: Gold complexes • C-S coupling • Zinc Finger protein
• MS • XAS
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Entry for the Table of Contents
COMMUNICATION
Raphael E. F. de Paiva, Zhifeng Du,
Douglas H. Nakahata, Frederico A.
Lima, Pedro P. Corbi and Nicholas P.
Farrell*
Page No. – Page No.
Au-catalyzed C-S aryl group transfer
in Zinc Finger Proteins
Schematic representation of the Au-catalyzed chemoselective Cys-arylation in a
zinc finger protein. The S-arylating agent is the organometallic compound [Au(2-
benzylyridine)Cl2].
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