A Helquat-like Compound as a Potent Inhibitor of Flaviviral and Coronaviral Polymerases

Konkoľová, Eva; Krejčová, Kateřina; Eyer, Luděk; Hodek, Jan; Zgarbová, Michala; Fořtová, Andrea; Jirásek, Michael; Teplý, Filip; Reyes‐Gutiérrez, Paul E.; Růžek, Daniel; Weber, Jan; Bouřa, Evžen

doi:10.3390/molecules27061894

Cited by 7 publications

(5 citation statements)

References 42 publications

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“…A pyridobenzothiazole compound, HeE1-2Tyr, initially characterized as an inhibitor of flavirus RdRp interacting with its RNA-binding sites [ 36 ], was shown to inhibit SARS-CoV-2 RdRp with IC 50 of 27 μM [ 37 ]. Furthermore, a helquat-like compound PR673 was shown to inhibit SARS-CoV-2 RdRp with IC 50 of ~4 μM [ 38 ]. However, the effects of both compounds on RNA binding by SARS-CoV-2 RdRp were not tested.…”

Section: Discussionmentioning

confidence: 99%

Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA

Matyugina

Petushkov

Суржиков

et al. 2023

IJMS

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The SARS-CoV-2 betacoronavirus pandemic has claimed more than 6.5 million lives and, despite the development and use of COVID-19 vaccines, remains a major global public health problem. The development of specific drugs for the treatment of this disease remains a very urgent task. In the context of a repurposing strategy, we previously screened a library of nucleoside analogs showing different types of biological activity against the SARS-CoV-2 virus. The screening revealed compounds capable of inhibiting the reproduction of SARS-CoV-2 with EC50 values in the range of 20–50 µM. Here we present the design and synthesis of various analogs of the leader compounds, the evaluation of their cytotoxicity and antiviral activity against SARS-CoV-2 in cell cultures, as well as experimental data on RNA-dependent RNA polymerase inhibition. Several compounds have been shown to prevent the interaction between the SARS-CoV-2 RNA-dependent RNA polymerase and the RNA substrate, likely inhibiting virus replication. Three of the synthesized compounds have also been shown to inhibit influenza virus. The structures of these compounds can be used for further optimization in order to develop an antiviral drug.

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Section: Discussionmentioning

confidence: 99%

Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA

Matyugina

Petushkov

Суржиков

et al. 2023

IJMS

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“…Takové umělé inteligence by byly přínosné zejména tam, kde je generování experimentálních krystalových struktur velmi náročné. Například zatímco identifikace inhibitorů virových polymeras, ať už jakoukoli metodou, je poměrně přímočará [78][79][80][81] , získání jejich krystalové struktury může být velmi náročné, protože je třeba připravit krystaly ternárního komplexu, který obsahuje také RNA a její sekvence musí být optimalizována. V takových situacích jsme se dříve často spoléhali na modely odvozené z počítačových simulací 82 .…”

Section: Budoucí Vývojunclassified

Structural Biology in Antiviral Research – A Story Illustrated by the Tales of Lipid Kinases, STING and Viral Methyltransferases

Bouřa

2023

Chem. Listy

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This article focuses on the role of structural biology in the development of small molecules that serve as protein ligands, which could potentially be used as drugs in the future. Experimental methods are utilized to obtain structural information about proteins, which then allow for virtual screening of extensive libraries of substances. The discovered ligands are further experimentally verified, with structural biology playing a crucial role in their refinement. The goal is to develop a ligand with high affinity and specificity, which could become an effective medicine. This is followed by the optimization of these substances from a chemical and pharmacological standpoint. The entire process is illustrated with examples from the recent past, such as lipid kinases, the stimulator of interferon genes (STING), and viral methyltransferases. Full text English translation is available in the on-line version.

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“…1C) which is structurally related to the title compound HeliDye1. 23 Helquat dye PR673 inhibited RNAdependent RNA polymerase (key enzyme for the replication of RNA viruses) of all seven tested viruses (including Zika, yellow fever and SARS-CoV-2 viruses). Later, in a study searching for anti-HIV-1 Inhibitors, we observed interaction of several helquat dyes with G-quadruplexes (manuscript in preparation).…”

Section: (D)mentioning

confidence: 99%

HeliDye1: helquat fluorogenic probe specific for AT-rich DNA duplexes

Kužmová

Joshi

Kozák

et al. 2022

Preprint

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DNA-binding fluorescent probes are useful tools in cell biology for various applications enabling visualisation and quantification of DNA. Herein, we report on HeliDye1, a novel cationic helicene-like DNA probe, and its versatile usability. HeliDye1 exhibits fluorescence exclusively in the presence of DNA duplexes containing AT base pairs and (contrary to any recent DNA probe) it remains non-fluorescent in the presence of single-stranded DNA and RNA. Favourable chemical properties of HeliDye1 allowed its use in karyotyping and super-resolution microscopy. We present five more applications of HeliDye1. Viscosimetry showed that HeliDye1 is a minor groove binder. HeliDye1 interacts with double-stranded DNA as an induced (P)-enantiomer, which we confirmed by ECD spectroscopy and DFT calculations. ECD spectroscopy suggested the formation of HeliDye1 dimers. MD simulations predicted the structures of (P)-HeliDye1 dimers inside DNA and showed their stability in AT-rich sequences and instability in GC-rich sequences.

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A Helquat-like Compound as a Potent Inhibitor of Flaviviral and Coronaviral Polymerases

Cited by 7 publications

References 42 publications

Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA

Nucleoside Analogs That Inhibit SARS-CoV-2 Replication by Blocking Interaction of Virus Polymerase with RNA

Structural Biology in Antiviral Research – A Story Illustrated by the Tales of Lipid Kinases, STING and Viral Methyltransferases

HeliDye1: helquat fluorogenic probe specific for AT-rich DNA duplexes

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