5-(Perylen-3-ylethynyl)uracil as an antiviral scaffold: Potent suppression of enveloped virus reproduction by 3-methyl derivatives in vitro

Amphipathic nucleoside and non-nucleoside derivatives of pentacyclic aromatic hydrocarbon perylene are known as potent non-cytotoxic broad-spectrum antivirals. Here we report 3-methyl-5-(perylen-3-ylethynyl)-uracil-1-acetic acid and its amides, a new series of compounds based on a 5-(perylen-3-yleth...

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Published in:Antiviral research 2023-01, Vol.209, p.105508-105508, Article 105508
Main Authors: Chistov, Alexey A., Chumakov, Stepan P., Mikhnovets, Igor E., Nikitin, Timofei D., Slesarchuk, Nikita A., Uvarova, Victoria I., Rubekina, Anna A., Nikolaeva, Yulia V., Radchenko, Eugene V., Khvatov, Evgeny V., Orlov, Alexey A., Frolenko, Vasilisa S., Sukhorukov, Maksim V., Kolpakova, Ekaterina S., Shustova, Elena Y., Galochkina, Anastasiya V., Streshnev, Philipp P., Osipov, Eugene M., Sapozhnikova, Ksenia A., Moiseenko, Andrey V., Brylev, Vladimir A., Proskurin, Gleb V., Dokukin, Yuri S., Kutyakov, Sergey V., Aralov, Andrey V., Korshun, Vladimir A., Strelkov, Sergei V., Palyulin, Vladimir A., Ishmukhametov, Aydar A., Shirshin, Evgeny A., Osolodkin, Dmitry I., Shtro, Anna A., Kozlovskaya, Liubov I., Alferova, Vera A., Ustinov, Alexey V.
Format: Article
Language:English
Subjects:
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Broad spectrum antivirals
COVID-19
Enveloped viruses
Fusion inhibitors
Humans
Perylene - pharmacology
Perylenylethynyluracil
Photosensitization
Respiratory viruses
SARS-CoV-2
Uracil - pharmacology
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Summary:Amphipathic nucleoside and non-nucleoside derivatives of pentacyclic aromatic hydrocarbon perylene are known as potent non-cytotoxic broad-spectrum antivirals. Here we report 3-methyl-5-(perylen-3-ylethynyl)-uracil-1-acetic acid and its amides, a new series of compounds based on a 5-(perylen-3-ylethynyl)-uracil scaffold. The compounds demonstrate pronounced in vitro activity against arthropod-borne viruses, namely tick-borne encephalitis virus (TBEV) and yellow fever virus (YFV), in plaque reduction assays with EC50 values below 1.9 and 1.3 nM, respectively, and Chikungunya virus (CHIKV) in cytopathic effect inhibition test with EC50 values below 3.2 μM. The compounds are active against respiratory viruses as well: severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in cytopathic effect inhibition test and influenza A virus (IAV) in virus titer reduction experiments are inhibited – EC50 values below 51 nM and 2.2 μM, respectively. The activity stems from the presence of a hydrophobic perylene core, and all of the synthesized compounds exhibit comparable 1O2 generation rates. Nonetheless, activity can vary by orders of magnitude depending on the hydrophilic part of the molecule, suggesting a complex mode of action. A time-of-addition experiment and fluorescent imaging indicate that the compounds inhibit viral fusion in a dose-dependent manner. The localization of the compound in the lipid bilayers and visible damage to the viral envelope suggest the membrane as the primary target. Dramatic reduction of antiviral activity with limited irradiation or under treatment with antioxidants further cements the idea of photoinduced ROS-mediated viral envelope damage being the mode of antiviral action. [Display omitted] •A series of novel perylen-based antivirals was designed and synthesized.•The compounds were shown to inhibit 5 enveloped viruses (TBEV,YFV,IAV,SARS-Cov-2,CHIKV).•1O2 generation and light dosing suggest photosensitizing mode of action.•Hydrophilic part of molecule can modulate activity by orders of magnitude.•The compounds inhibit fusion and damage viral envelope.
ISSN:0166-3542
1872-9096
DOI:10.1016/j.antiviral.2022.105508