Presentation of the team - Institut Curie
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Molecular recognition of nucleic acids
UMR9187 / U1196 – Chemistry, Modelling and Imaging for Biology
(CMIB)
Anton Granzhan
Molecular recognition of nucleic acids
anton.granzhan@curie.fr
Tel: +33 (0)1 69 86 30 89
Presentation of the team
The main missions of our team include the design, synthesis, and studies of novel small-
molecule ligands and probes able to recognize unusual DNA and RNA structures (in particular,
damaged DNA structures representing intermediates in enzymatic DNA repair), as well as
elucidation of their biological effects in cellular models. We assume that these compounds could
interfere with the native functions of nucleic acids or enzymatic DNA repair, thereby finding
applications in cancer therapy.
Recognition of pairing defects in double-stranded DNA
Recognition of DNA mismatches and ligand control of DNA hybridization: We developed
a family of distance-constrained polyazacyclophane macrocycles (also termed
cyclobisintercalators), a unique series of DNA ligands whose very particular geometry results in
enhanced binding to DNA pairing defects, such as mismatched base pairs and abasic sites in
double-stranded DNA. In a collaboration with Muriel Jourdan (Grenoble), we investigated the
structural details of the recognition of thymine–thymine (T-T) mismatches by these macrocycles
using high-resolution NMR spectroscopy. More recently, we demonstrated that their unique DNA-
binding properties could be exploited for a controlled modulation of the hybridization state of
mismatch-containing DNA duplexes. Thus, hybridization of DNA strands containing multiple T-T
mismatches can be induced at room temperature through addition of a stoichiometric amount of
the macrocycle. Moreover, this process can be reversibly controlled by addition or sequestration
of copper(II) cations, which capture the ligand in a non-DNA-binding, dinuclear metal complex.
This mechanism allows implementation of reversible DNA switches and machines.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1
Molecular recognition of nucleic acids
UMR9187 / U1196 – Chemistry, Modelling and Imaging for Biology
(CMIB)
Kotera, N.; Guillot, R.; Teulade-Fichou, M.-P; Granzhan, A.* Copper(II)-Controlled Molecular Glue
for Mismatched DNA. ChemBioChem 2017, 7, 618–622.
Review: Granzhan, A.;* Kotera, N.; Teulade-Fichou, M.-P.* Finding needles in a basestack:
recognition of mismatched base pairs in DNA by small molecules. Chem. Soc. Rev. 2014, 43,
3630–3665.
Jourdan, M.; Granzhan, A.; Guillot, R.; Dumy, P.; Teulade-Fichou, M.-P.* Double Threading
through DNA: NMR Structural Study of a Bis-Naphthalene Macrocycle Bound to a
Thymine–Thymine Mismatch. Nucleic Acids Res. 2012, 40, 5115–5128.
Granzhan, A.; Largy, E.; Saettel, N.; Teulade‑Fichou, M.-P.* Macrocyclic DNA-Mismatch-Binding
Ligands: Structural Determinants of Selectivity. Chem. Eur. J. 2010, 16, 878–889.
Recognition of abasic sites and inhibition of DNA repair: Small-molecule recognition of
another type of DNA pairing defects, namely abasic sites, can be harnessed to induce
modulation of enzymatic DNA repair pathways. In particular, we showed that binding of
macrocyclic ligands to abasic sites leads to efficient inhibition of the cleavage of the latter by
human AP endonuclease 1 (APE1) via a substrate-masking mechanism (“indirect” inhibition),
with IC50 values comparable to the best APE1 inhibitors acting on the protein itself. Thus,
substrate masking by non-covalent abasic-site ligands represents an attractive strategy for
inhibition of APE1. Moreover, with a native abasic site substrate, the APE1 inhibition effect of the
macrocycle is accompanied by the enzyme-independent cleavage of the DNA substrate by the
ligand per se through another mechanism (β-elimination). Altogether, the ligand shifts the
processing of abasic sites from the APE1-induced cleavage (hydrolysis of the phophodiester bond
at the abasic site) to AP lyase-like cleavage (cleavage of the C3′–O-P bond). Thus, these ligands
can be considered as promising modulators of cellular DNA repair pathways and represent a
potential for anti-cancer therapy in a combination with DNA-targeting drugs.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2
Molecular recognition of nucleic acids
UMR9187 / U1196 – Chemistry, Modelling and Imaging for Biology
(CMIB)
Caron, C.; Duong, X. N. T.; Guillot, R.; Bombard, S.; Granzhan, A.* Interaction of Functionalized
Naphthalenophanes with Abasic Sites in DNA: DNA Cleavage, DNA Cleavage Inhibition, and
Formation of Ligand–DNA Adducts. Chem. Eur. J. 2019, 25, 1949–1962.
Kotera, N.; Granzhan, A.;* Teulade-Fichou, M.-P. Comparative study of affinity and selectivity of
ligands targeting abasic and mismatch sites in DNA using a fluorescence-melting assay.
Biochimie 2016, 128–129, 133–137.
Kotera, N.; Poyer, F.; Granzhan, A.;* Teulade-Fichou, M.-P. Efficient inhibition of human AP endo-
nuclease 1 (APE1) via substrate masking by abasic site-binding macrocyclic ligands. Chem.
Commun. 2015, 51, 15948–15951.
Fluorescent probes for G-quadruplex DNA structures
Development of fluorescent probes for G-quadruplex (G4) DNA and RNA structures remains an
active research area due to the high biological importance of these non-canonical nucleic acid
structures, which is still far from being fully understood. Along these lines, we demonstrated that
2,4-distyrylpyridinium dyes (e.g., 1a and analogues) represent an easily available and highly
promising scaffold for G4-DNA-selective fluorescent probes with excellent optical properties.
Additionally, we established a novel bimodal (colorimetric and fluorimetric) probe BCVP, useful
for robust in vitro detection of G4-DNA structures irrespective of their topology and their
discrimination from other DNA forms.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3Molecular recognition of nucleic acids
UMR9187 / U1196 – Chemistry, Modelling and Imaging for Biology
(CMIB)
Xie, X.; Zuffo, M.; Teulade-Fichou, M.-P.; Granzhan, A.* Identification of optimal fluorescent
probes for G‑quadruplex nucleic acids through systematic exploration of mono- and distyryl
dye libraries. Beilstein J. Org. Chem. 2019, 15, 1872–1889. PDF (CC-BY)
Xie, X.; Reznichenko, O.; Chaput, L.; Martin, P.; Teulade-Fichou, M.-P.; Granzhan, A.* Topology‐
Selective, Fluorescent “Light‐Up” Probes for G‐Quadruplex DNA Based on Photoinduced
Electron Transfer. Chem. Eur. J. 2018, 24, 12638-12651.
Xie, X.; Renvoisé, A.; Granzhan, A.;* Teulade-Fichou, M.-P. Aggregating distryrylpyridinium dye
as a bimodal structural probe for G-quadruplex DNA. New J. Chem. 2015, 39, 5931–5935.
Xie, X.; Choi, B.; Largy, E.; Guillot, R.; Granzhan, A.; Teulade-Fichou, M.-P.* Asymmetric Distyryl-
pyridinium Dyes as Red-Emitting Fluorescent Probes for Quadruplex DNA. Chem. Eur. J. 2013,
19, 1214–1226.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 4Molecular recognition of nucleic acids
UMR9187 / U1196 – Chemistry, Modelling and Imaging for Biology
(CMIB)
Key publications
Year of publication 2019
Xiao Xie, Michela Zuffo, Marie-Paule Teulade-Fichou, Anton Granzhan (2019 Aug 6)
Identification of optimal fluorescent probes for G-quadruplex nucleic acids
through systematic exploration of mono- and distyryl dye libraries
Beilstein Journal of Organic Chemistry : 15 : 1872–1889 : DOI : 10.3762/bjoc.15.183
Oksana Reznichenko, Alicia Quillévéré, Rodrigo Prado Martins, Nadège Loaëc, Hang Kang, María
José Lista, Claire Beauvineau, Jorge González-García, Régis Guillot, Cécile Voisset, Chrysoula
Daskalogianni, Robin Fåhraeus, Marie-Paule Teulade-Fichou, Marc Blondel, Anton Granzhan
(2019 May 23)
Novel cationic bis(acylhydrazones) as modulators of Epstein–Barr virus immune
evasion acting through disruption of interaction between nucleolin and G-
quadruplexes of EBNA1 mRNA
European Journal of Medicinal Chemistry : 178 : 13-29 : DOI : 10.1016/j.ejmech.2019.05.042
Coralie Caron, Xuan N T Duong, Régis Guillot, Sophie Bombard, Anton Granzhan (2019 Feb 6)
Interaction of Functionalized Naphthalenophanes with Abasic Sites in DNA: DNA
Cleavage, DNA Cleavage Inhibition, and Formation of Ligand-DNA Adducts.
Chemistry - A European Journal : 25 : 1949–1962 : DOI : 10.1002/chem.201805555
Michela Zuffo, Xiao Xie, Anton Granzhan (2018 Dec 6)
Strength in Numbers: Development of a Fluorescence Sensor Array for
Secondary Structures of DNA.
Chemistry - A European Journal : 25 : 1812–1818 : DOI : 10.1002/chem.201805422
Year of publication 2018
Abhijit Saha, Sophie Bombard, Anton Granzhan, Marie-Paule Teulade-Fichou (2018 Oct 27)
Probing of G-Quadruplex Structures via Ligand-Sensitized Photochemical
Reactions in BrU-Substituted DNA.
Scientific Reports : 8 : 15814 : DOI : 10.1038/s41598-018-34141-z
Xiao Xie, Oksana Reznichenko, Ludovic Chaput, Pascal Martin, Marie-Paule Teulade-Fichou,
Anton Granzhan (2018 Aug 27)
Topology-Selective Fluorescent “Light-Up” Probes for G-Quadruplex DNA Based
on Photoinduced Electron Transfer.
Chemistry - A European Journal : 24 : 12638-12651 : DOI : 10.1002/chem.201801701
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 5Molecular recognition of nucleic acids
UMR9187 / U1196 – Chemistry, Modelling and Imaging for Biology
(CMIB)
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