Simplistic perylene-related compounds as inhibitors of tick-borne encephalitis virus reproduction

Slesarchuk, Nikita A.; Khvatov, Evgeny V.; Chistov, Alexey A.; Proskurin, Gleb V.; Nikitin, Timofei D.; Lazarevich, Anastasiya I.; Ulanovskaya, Angelina A.; Ulashchik, Egor; Orlov, Alexey A.; Jegorov, Artjom V.; Ustinov, A. V.; Tyurin, Anton P.; Shmanai, Vadim V.; Ishmukhametov, Aydar A.; Korshun, Vladimir A.; Osolodkin, Dmitry I.; Kozlovskaya, Liubov I.; Aralov, Andrey V.

doi:10.1016/j.bmcl.2020.127100

Cited by 18 publications

(18 citation statements)

References 33 publications

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“…However, further studies revealed that their structures could be significantly simplified, and neither the nucleobase nor the carbohydrate moiety were vital for their antiviral action [ 28 ]. Thorough structural studies led to the development of perylene-based compounds with remarkable subnanomolar in vitro activity against a wide range of enveloped viruses [ 29 ]. The mechanism of viral fusion inhibition by perylene derivatives is not yet completely understood.…”

Section: Introductionmentioning

confidence: 99%

Cationic Perylene Antivirals with Aqueous Solubility for Studies In Vivo

et al. 2022

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Perylene-based compounds are attracting significant attention due to their high broad-spectrum antiviral activity against enveloped viruses. Despite unambiguous results of in vitro studies and high selectivity index, the poor water solubility of these compounds prevented in vivo evaluation of their antiviral properties. In this work, we synthesized a series of compounds with a perylene pharmacophore bearing positively charged substituents to improve the aqueous solubility of this unique type of antivirals. Three types of charged groups were introduced: (1) quaternary morpholinium salts (3a–b); (2) a 2′-O-l-valinyl-uridine hydrochloride residue (8), and (3) a 3-methylbenzothiazolium cation (10). The synthesized compounds were evaluated based both on antiviral properties in vitro (CHIKV, SARS-CoV-2, and IAV) and on solubility in aqueous media. Compound 10 has the greatest aqueous solubility, making it preferable for pre-evaluation by intragastrical administration in a mouse model of lethal influenza pneumonia. The results indicate that the introduction of a positively charged group is a viable strategy for the design of drug candidates with a perylene scaffold for in vivo studies.

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Section: Introductionmentioning

confidence: 99%

Cationic Perylene Antivirals with Aqueous Solubility for Studies In Vivo

et al. 2022

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“…Compounds 18 and 21 showed high activity (EC 50 20–25 nM) against tick-borne encephalitis virus (TBEV) [ 97 ]. Subsequently, numerous perylene derivatives (e.g., 22 – 30 ) ( Figure 7 ) were synthesized [ 98 , 99 , 100 , 101 ], showing high activity against TBEV (EC 50 up to < 1 nM) and HSV, as well as African swine fever virus [ 102 ] and respiratory viruses [ 103 ]. The structural diversity of antiviral perylene compounds and their action exclusively against enveloped viruses with little cytotoxicity is obvious evidence in favor of the fact that the targets of such substances are the lipids of the virion envelope.…”

Section: Perylene-based Rigid Amphipathic Photosensitizersmentioning

confidence: 99%

Photosensitizing Antivirals

et al. 2021

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Antiviral action of various photosensitizers is already summarized in several comprehensive reviews, and various mechanisms have been proposed for it. However, a critical consideration of the matter of the area is complicated, since the exact mechanisms are very difficult to explore and clarify, and most publications are of an empirical and “phenomenological” nature, reporting a dependence of the antiviral action on illumination, or a correlation of activity with the photophysical properties of the substances. Of particular interest is substance-assisted photogeneration of highly reactive singlet oxygen (1O2). The damaging action of 1O2 on the lipids of the viral envelope can probably lead to a loss of the ability of the lipid bilayer of enveloped viruses to fuse with the lipid membrane of the host cell. Thus, lipid bilayer-affine 1O2 photosensitizers have prospects as broad-spectrum antivirals against enveloped viruses. In this short review, we want to point out the main types of antiviral photosensitizers with potential affinity to the lipid bilayer and summarize the data on new compounds over the past three years. Further understanding of the data in the field will spur a targeted search for substances with antiviral activity against enveloped viruses among photosensitizers able to bind to the lipid membranes.

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“…Heliomycin (also known as resistomycin) was identified as a secondary metabolite produced by Streptomyces resistomycificus and has been reported to have antiviral [1, 2], antifungal [3], antibacterial [4], antimicrobial, RNA synthesis-inhibiting [5], and HIV-1 protease-suppressing [6] activities. It also possesses cytotoxicity against cancer cells from different tissues, such as cervical, gastric, hepatic, and breast cancers [4, 7-9].…”

Section: Introductionmentioning

confidence: 99%

Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells

Islam

Chen

Weng

et al. 2023

Preprint

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The antibiotic heliomycin (resistomycin), which is generated fromStreptomyces resistomycificus, has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives of heliomycin were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, but the drug targets remained unknown. In this study, we conducted cellular thermal shift assays and molecular docking simulations to identify and validate the intracellular targets of heliomycin and its water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH), in p53-functional SAS and p53-mutated HSC-3 oral cancer cells. Consistent with ourin silicostudies, our cellular thermal shift assays (CETSA) revealed that, in addition to SIRT1, the water-soluble 4-dmH preferentially targeted a tumor-associated NADH oxidase called tNOX or ENOX2. The direct binding of 4-dmH to tNOX inhibited the activity of tNOX and enhanced its ubiquitin-proteasomal protein degradation in both SAS and HSC-3 cells. Moreover, the inhibition of tNOX by 4-dmH decreased the oxidation of NADH to NAD+which diminished NAD+-dependent SIRT1 deacetylase activity, ultimately inducing apoptosis and significant cytotoxicity in both cell types. We also observed that tNOX and SIRT1 were both upregulated in tumor tissues of oral cancer patients compared to adjacent normal tissues, suggesting their clinical relevance. Finally, the better therapeutic efficacy of 4-dmH was confirmed in tumor-bearing mice, which showed greater tNOX and SIRT1 downregulation and tumor volume reduction when treated with 4-dmH compared to heliomycin. Taken together, ourin vitroandin vivofindings suggest that the multifaceted properties of water-soluble 4-dmH enable it to offer superior antitumor value compared to parental heliomycin, and indicated that it functions through targeting the tNOX-NAD+-SIRT1 axis to induce apoptosis in oral cancer cells.

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Simplistic perylene-related compounds as inhibitors of tick-borne encephalitis virus reproduction

Cited by 18 publications

References 33 publications

Cationic Perylene Antivirals with Aqueous Solubility for Studies In Vivo

Cationic Perylene Antivirals with Aqueous Solubility for Studies In Vivo

Photosensitizing Antivirals

Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells

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