Anders Foller Füchtbauer

University of Gothenburg

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Morten Grøtli

University of Gothenburg

L. Marcus Wilhelmsson

Chalmers University of Technology

Moa S. Wranne

Chalmers University of Technology

Mattias Bood

AstraZeneca (Sweden)

Tom Brown

ATDBio (United Kingdom)

Afaf H. El‐Sagheer

University of Southampton

Anders Dahlén

AstraZeneca (Sweden)

Josipa Matić

Rudjer Boskovic Institute

Sangamesh Sarangamath

Chalmers University of Technology

Henrik Gradén

AstraZeneca (Sweden)

Cooperative Institutions

Chalmers University of Technology

University of Gothenburg

KTH Royal Institute of Technology

Science for Life Laboratory

University of Cambridge

Stanford University

Göteborgs Stads

Suez University

Suez Canal University

University of Southampton

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Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase

European Journal of Medicinal Chemistry (2022)

Amalyn Nain‐Perez Anders Foller Füchtbauer Liliana Håversen Aleksei Lulla Chunxia Gao

Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound. A structure–activity relationship study of 47 novel synthetic derivatives revealed PKL inhibitors with half-maximal inhibitory concentration (IC50) values in the 200 nM range. Despite the difficulty involved in studying a binding site as exposed as the ADP site, these derivatives feature expanded structural diversity and chemical spaces that may be used to improve their inhibitory activities against PKL. The obtained results expand the knowledge of the structural requirements for interactions with the ADP-binding site of PKL.

10.1016/j.ejmech.2022.114270

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Citations (10)

Getting DNA and RNA out of the dark with 2CNqA: a bright adenine analogue and interbase FRET donor

Nucleic Acids Research (2020)

Anna Wypijewska del Nogal Anders Foller Füchtbauer Mattias Bood Jesper R. Nilsson Moa S. Wranne

Abstract With the central role of nucleic acids there is a need for development of fluorophores that facilitate the visualization of processes involving nucleic acids without perturbing their natural properties and behaviour. Here, we incorporate a new analogue of adenine, 2CNqA, into both DNA and RNA, and evaluate its nucleobase-mimicking and internal fluorophore capacities. We find that 2CNqA displays excellent photophysical properties in both nucleic acids, is highly specific for thymine/uracil, and maintains and slightly stabilises the canonical conformations of DNA and RNA duplexes. Moreover, the 2CNqA fluorophore has a quantum yield in single-stranded and duplex DNA ranging from 10% to 44% and 22% to 32%, respectively, and a slightly lower one (average 12%) inside duplex RNA. In combination with a comparatively strong molar absorptivity for this class of compounds, the resulting brightness of 2CNqA inside double-stranded DNA is the highest reported for a fluorescent base analogue. The high, relatively sequence-independent quantum yield in duplexes makes 2CNqA promising as a nucleic acid label and as an interbase Förster resonance energy transfer (FRET) donor. Finally, we report its excellent spectral overlap with the interbase FRET acceptors qAnitro and tCnitro, and demonstrate that these FRET pairs enable conformation studies of DNA and RNA.

10.1093/nar/gkaa525

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Synthesis, oligonucleotide incorporation and fluorescence properties in DNA of a bicyclic thymine analogue

Scientific Reports (2018)

Christopher P. Lawson Anders Foller Füchtbauer Moa S. Wranne Tristan Giraud Tom Floyd

Abstract Fluorescent base analogues (FBAs) have emerged as a powerful class of molecular reporters of location and environment for nucleic acids. In our overall mission to develop bright and useful FBAs for all natural nucleobases, herein we describe the synthesis and thorough characterization of bicyclic thymidine (bT), both as a monomer and when incorporated into DNA. We have developed a robust synthetic route for the preparation of the bT DNA monomer and the corresponding protected phosphoramidite for solid-phase DNA synthesis. The bT deoxyribonucleoside has a brightness value of 790 M −1 cm −1 in water, which is comparable or higher than most fluorescent thymine analogues reported. When incorporated into DNA, bT pairs selectively with adenine without perturbing the B-form structure, keeping the melting thermodynamics of the B-form duplex DNA virtually unchanged. As for most fluorescent base analogues, the emission of bT is reduced inside DNA (4.5- and 13-fold in single- and double-stranded DNA, respectively). Overall, these properties make bT an interesting thymine analogue for studying DNA and an excellent starting point for the development of brighter bT derivatives.

Thymine

10.1038/s41598-018-31897-2

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Citations (12)

Pulse-shaped two-photon excitation of a fluorescent base analogue approaches single-molecule sensitivity

Physical Chemistry Chemical Physics (2018)

Rachel S. Fisher David Nobis Anders Foller Füchtbauer Mattias Bood Morten Grøtli

Fluorescent nucleobase analogues (FBAs) have many desirable features in comparison to extrinsic fluorescent labels, but they are yet to find application in ultrasensitive detection. Many of the disadvantages of FBAs arise from their short excitation wavelengths (often in the ultraviolet), making two-photon excitation a potentially attractive approach. Pentacyclic adenine (pA) is a recently developed FBA that has an exceptionally high two-photon brightness. We have studied the two-photon-excited fluorescence properties of pA and how they are affected by incorporation in DNA. We find that pA is more photostable under two-photon excitation than via resonant absorption. When incorporated in an oligonucleotide, pA has a high two-photon cross section and emission quantum yield, varying with sequence context, resulting in the highest reported brightness for such a probe. The use of a two-photon microscope with ultrafast excitation and pulse shaping has allowed the detection of pA-containing oligonucleotides in solution with a limit of detection of ∼5 molecules, demonstrating that practical single-molecule detection of FBAs is now within reach.

Two-photon excitation microscopy

Quantum yield

10.1039/c8cp05496g

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Citations (19)

Lighting Up DNA with the Environment‐Sensitive Bright Adenine Analogue qAN4

ChemPlusChem (2020)

Anders Foller Füchtbauer Moa S. Wranne Sangamesh Sarangamath Mattias Bood Afaf H. El‐Sagheer

Abstract The fluorescent adenine analogue qAN4 was recently shown to possess promising photophysical properties, including a high brightness as a monomer. Here we report the synthesis of the phosphoramidite of qAN4 and its successful incorporation into DNA oligonucleotides using standard solid‐phase synthesis. Circular dichroism and thermal melting studies indicate that the qAN4‐modification has a stabilizing effect on the B‐form of DNA. Moreover, qAN4 base‐pairs selectively with thymine with mismatch penalties similar to those of mismatches of adenine. The low energy absorption band of qAN4 inside DNA has its peak around 358 nm and the emission in duplex DNA is partly quenched and blue‐shifted (ca. 410 nm), compared to the monomeric form. The spectral properties of the fluorophore also show sensitivity to pH; a property that may find biological applications. Quantum yields in single‐stranded DNA range from 1–29 % and in duplex DNA from 1–7 %. In combination with the absorptive properties, this gives an average brightness inside duplex DNA of 275 M −1 cm −1 , more than five times higher than the most used environment‐sensitive fluorescent base analogue, 2‐aminopurine. Finally, we show that qAN4 can be used to advantage as a donor for interbase FRET applications in combination with adenine analogue qA nitro as an acceptor.

Phosphoramidite

Acceptor

Thymine

10.1002/cplu.201900712

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Citations (5)

Flexibility and Preorganization of Fluorescent Nucleobase-Pyrene Conjugates Control DNA and RNA Recognition

Molecules (2020)

Željka Ban Josipa Matić Mladen Žinić Anders Foller Füchtbauer L. Marcus Wilhelmsson

We synthesized a new amino acid-fluorescent nucleobase derivative (qAN1-AA) and from it two new fluorescent nucleobase–fluorophore (pyrene) conjugates, whereby only the analogue with the longer and more flexible linker (qAN1-pyr2) self-folded into intramolecularly stacked qAN1/pyrene conformation, yielding characteristic, 100 nm-red-shifted emission (λmax = 500 nm). On the contrary, the shorter and more rigid linker resulted in non-stacked conformation (qAN1-pyr1), characterized by the emission of free pyrene at λmax = 400 nm. Both fluorescent nucleobase–fluorophore (pyrene) conjugates strongly interacted with ds-DNA/RNA grooves with similar affinity but opposite fluorescence response (due to pre-organization), whereas the amino acid-fluorescent base derivative (qAN1-AA) was inactive. However, only intramolecularly self-folded qAN1-pyr2 showed strong fluorescence selectivity toward poly U (Watson–Crick complementary to qAN1 nucleobase) and poly A (reverse Hoogsteen complementary to qAN1 nucleobase), while an opposite emission change was observed for non-complementary poly G and poly C. Non-folded analogue (qAN1-pyr1) showed no ss-RNA selectivity, demonstrating the importance of nucleobase-fluorophore pre-organization.

Nucleobase

Linker

10.3390/molecules25092188

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Citations (10)

Fluorescent RNA cytosine analogue – an internal probe for detailed structure and dynamics investigations

Scientific Reports (2017)

Anders Foller Füchtbauer Søren Preus Karl Börjesson Scott A. McPhee David M.J. Lilley

The bright fluorescent cytosine analogue tC

Cytosine

Quantum yield

Duplex (building)

10.1038/s41598-017-02453-1

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Citations (24)

Interbase FRET in RNA: from A to Z

Nucleic Acids Research (2019)

Anders Foller Füchtbauer Moa S. Wranne Mattias Bood Erik Weis Pauline Pfeiffer

Abstract Interbase FRET can reveal highly detailed information about distance, orientation and dynamics in nucleic acids, complementing the existing structure and dynamics techniques. We here report the first RNA base analogue FRET pair, consisting of the donor tCO and the non-emissive acceptor tCnitro. The acceptor ribonucleoside is here synthesised and incorporated into RNA for the first time. This FRET pair accurately reports the average structure of A-form RNA, and its utility for probing RNA structural changes is demonstrated by monitoring the transition from A- to Z-form RNA. Finally, the measured FRET data were compared with theoretical FRET patterns obtained from two previously reported Z-RNA PDB structures, to shed new light on this elusive RNA conformation.

Single-molecule FRET

Nucleic acid structure

Acceptor

10.1093/nar/gkz812

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Citations (26)

Sulfone-based human liver pyruvate kinase inhibitors – Design, synthesis and in vitro bioactivity

European Journal of Medicinal Chemistry (2024)

Josipa Matić Fady Akladios Umberto Maria Battisti Liliana Håversen Amalyn Nain‐Perez

Non-alcoholic fatty liver disease (NAFLD) is a prevalent pathological condition characterised by the accumulation of fat in the liver. Almost one-third of the global population is affected by NAFLD, making it a significant health concern. However, despite its prevalence, there is currently no approved drug specifically designed for the treatment of NAFLD. To address this critical gap, researchers have been investigating potential targets for NAFLD drug development. One promising candidate is the liver isoform of pyruvate kinase (PKL). In recent studies, Urolithin C, an allosteric inhibitor of PKL, has emerged as a potential lead compound for therapeutic intervention. Building upon this knowledge, our team has conducted a comprehensive structure-activity relationship of Urolithin C. In this work, we have employed a scaffold-hopping approach, modifying the urolithin structure by replacing the urolithin carbonyl with a sulfone moiety. Our structure-activity relationship analysis has identified the sulfone group as particularly favourable for potent PKL inhibition. Additionally, we have found that the presence of catechol moieties on the two aromatic rings further improves the inhibitory activity. The most promising inhibitor from this new series displayed nanomolar inhibition, boasting an IC

Druggability

Structure–activity relationship

10.1016/j.ejmech.2024.116306

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Pentacyclic adenine: a versatile and exceptionally bright fluorescent DNA base analogue

Chemical Science (2018)

Mattias Bood Anders Foller Füchtbauer Moa S. Wranne Jong Jin Ro Sangamesh Sarangamath

Emissive base analogs are powerful tools for probing nucleic acids at the molecular level. Herein we describe the development and thorough characterization of pentacyclic adenine (pA), a versatile base analog with exceptional fluorescence properties. When incorporated into DNA, pA pairs selectively with thymine without perturbing the B-form structure and is among the brightest nucleobase analogs reported so far. Together with the recently established base analog acceptor qAnitro, pA allows accurate distance and orientation determination via Förster resonance energy transfer (FRET) measurements. The high brightness at emission wavelengths above 400 nm also makes it suitable for fluorescence microscopy, as demonstrated by imaging of single liposomal constructs coated with cholesterol-anchored pA-dsDNA, using total internal reflection fluorescence microscopy. Finally, pA is also highly promising for two-photon excitation at 780 nm, with a brightness (5.3 GM) that is unprecedented for a base analog.

Base (topology)

10.1039/c7sc05448c

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Citations (39)