Development of antiviral therapeutics combating coxsackievirus type B3 infection

Enteroviruses comprise highly diverse group of single-stranded positive RNA viruses belonging to Enterovirus genus, Picornaviridae family. They are the most prevalent viruses worldwide highlighted by high resistance to environmental cues. Enteroviruses normally cause seasonal self-limiting infections, but also known as causative infectious agents of encephalitis, myocarditis, poliomyelitis, acute heart failure and sepsis. Enterovirus genetic plasticity contributes to widespread epidemics and sporadic outbreaks (e. g., outbreaks of Enterovirus D68 and Enterovirus 71). Type B Coxsackieviruses of Enterovirus B species is one of commonly identified infectious agents associated predominantly with mild upper respiratory and gastrointestinal illnesses. Nevertheless, Coxsackieviruses B3 infection can result in severe myocarditis leading ultimately to heart failure. The pathogenesis of Coxsackievirus B3-induced myocarditis is well known being mediated by both direct damage due to viral proteases and indirectly via secondary host immune responses. Despite success in preventive vaccination of some enterovirus infections that allowed to control some of them direct antiviral agents for treatment of enteroviral infection particularly Coxsackieviruses B3 myocardial infection are still in demand. In addition, no ongoing clinical trials for therapy or prevention of Coxsackieviruses B3 infection are available. Current treatment strategies are mainly aimed to stabilize patient condition and relieve discomfort condition. It seems that relatively small market for anti-enteroviral drugs prevents pharma industry from developing new drugs. The Coxsackieviruses B3 lifecycle have been extensively studied and potential targets for drug design have been identified. The aim of our review was to describe current state in the field of antiviral drug design combating Coxsackieviruses B3 infection emphasizing direct-acting antivirals, albeit paying some attention to host factor-targeting inhibitors (including compounds from medicinal plant extracts) as well. The following categories of direct Coxsackieviruses B3 inhibitors are discussed in detail: capsid binders (pleconaril and its derivatives), viral 3C protease inhibitors (rupintrivir and its analogs), drugs targeting viral replication (both nucleoside analogs and non-nucleoside inhibitors). Results of drug repurposing screens for amiloride, benzerazide, dibucaine and fluoxetine are also discussed

(2SR,3RS)-Methyl 2-(adamantan-1-yl)-3-phenyl­sulfonyl-3-(pyridin-2-ylsulfan­yl)propano­ate dichloro­methane hemisolvate

The title compound, C25H29NO4S2 0.5CH2Cl2, was obtained as a racemate. The pyridine and phenyl rings are arranged face-to-face, giving a weak intra­molecular π–π inter­action [centroid–centroid separation = 3.759 (3) Å]. These inter­actions are extended inter­molecularly, forming chains of stacked rings along [001] with separations of 3.859 (3) and 3.916 (3) Å. The solvent used for crystallization, CH2Cl2, is located in voids between the chains of mol­ecules, with a site occupancy of 0.5

Implementation of the program of measles elimination in the WHO African region

The review is devoted to the analysis of the available literature on the elimination of measles. The review focuses on the current measles epidemic situation in the African Region (AFR) and the implementation of the WHO strategic plan for the elimination of measles in AFR by 2020. Measles in the AFR is characterized by a severe course with a high risk of death due to malnutrition, vitamin A deficiency, concomitant bacterial and viral infections, and malaria. In 2015, 105,256 cases of measles were reported in the WHO African Region, most of them among children under 5 years old, 79% of whom were not vaccinated or had unknown vaccine status. Initially, the strategy for implementing the measles elimination program in AFRs was based on a combination of immunization campaigns for children under 14 years of age (coverage of more than 90%) and routine vaccination of at least 90% of children aged 9–15 months. It was recommended to repeat the campaign of mass immunization of children aged 9 months up to 4 years every 3–5 years. The use of this strategy has reduced the number of measles cases by 83–97% during the first year of additional immunization programs. The recommended age of routine measles vaccination in AFRs is 9 months — a strategy to reduce infant mortality, including that due to complications of measles. In 2016, measles vaccination was introduced into the national immunization schedule in all AFR countries, and 24 countries introduced revaccination. Currently, the measles elimination program in a number of AFR countries is based on two-dose immunization (MCV1 and MCV2). The measles prevention program in a number of AFR countries was disrupted due to the Ebola epidemic. There are some common problems in the realization of the program in AFR countries. All AFR countries are committed to the measles elimination program. The review provides information on strategies and successes in overcoming challenges to achieve the goals set for the WHO African Region in the implementation of the programme of measles elimination

ANTIVIRAL PROPERTIES OF VERDAZYLS AND LEUCOVERDAZYLS AND THEIR ACTIVITY AGAINST GROUP B ENTEROVIRUSES

Enteroviruses are non-enveloped viruses of Enterovirus genus, Picornaviridae family, causing a variety of human diseases: from acute respiratory and intestinal infections to more severe pathologies including poliomyelitis, encephalitis, myocarditis, pancreatitis. Currently, no approved direct-acting antiviral drugs for treatment of enterovirus infections exists, whereas vaccination is available only for prevention of poliomyelitis and enterovirus 71 infection. Therefore, it is promising to conduct a search for inhibitors of enteroviruses life cycle in drug development to treat enterovirus infections. Here, antiviral properties of stable free radicals, verdazyls, and their precursors, leucoverdazyls, were investigated. It has been shown that leucoverdazyls vs verdazyls increased the survival of permissive cell culture infected with coxsackievirus. The activity range of the lead leucoverdazyl against RNA-containing and DNA-containing human viruses (in the viral yield reduction assay) and its proposed mechanism of action (time of addition assay) was studied. The lead compound suppressed reproduction of group B enteroviruses in vitro, with modest activity against influenza A virus and no activity against herpes virus type 1 and adenovirus type 5. The maximum decrease in viral titers was observed upon its addition to infected cells during early and middle stages of the virus life cycle. Thus, we concluded that the studied compound has a pronounced inhibitory activity against group B enteroviruses not belonging to the class of capsid binder inhibitors, without virucidal properties. Previously, we described antioxidant properties of leucoverdazyls. It is known that many viral infections are accompanied by production of reactive oxygen species and oxidative stress, and some compounds with antioxidant properties exhibit antiviral potential. Targeted chemical modifications of leucoverdazyls and further studies of leucoverdazyl mechanism of action as well as in vivo animal studies are needed. However, the results obtained may be useful for future development of new antiviral drugs to treat enteroviral infections. © Volobueva A.S. et al., 2023.The work was supported by a grant for young scientists from the St. Petersburg Pasteur Institute

Natural products from medicinal plants in Asia and the Pacific for RNA viruses: Hercules’ fifth labour

Context: The emergence of zoonotic viruses in the last decades culminating with COVID-19 and challenges posed by the resistance of RNA viruses to antiviral drugs requires the development of new antiviral drugs. Objective: This review identifies natural products isolated from Asian and Pacific medicinal plants with in vitro and in vivo antiviral activity towards RNA viruses and analyses their distribution, molecular weights, solubility and modes of action. Materials and methods: All data in this review was compiled from Google Scholar, PubMed, Science Direct, Web of Science, ChemSpider, PubChem and library search from 1961 to 2022. Results: Out of about 350 molecules identified, 43 phenolics, 31 alkaloids, and 28 terpenes were very strongly active against at least one type of RNA virus. These natural products are mainly planar and amphiphilic, with a molecular mass between 200 and 400 g/mol and target viral genome replication. Hydroxytyrosol, silvestrol, lycorine, tylophorine and 12-O-tetradecanoylphorbol 13-acetate with IC50 below 0.01 mg/mL and selectivity index (S.I.) above 100 have the potential to be used for the development of anti-RNA virus leads. Discussion and conclusions: The medicinal plants of Asia and the Pacific are a rich source of natural products with the potential to be developed as lead for the treatment of RNA viral infections

4-Hydroxy-3-nitro-1,4-dihydrotriazolo[5,1-c][1,2,4]triazines: synthesis, antiviral activity, and electrochemical characteristics

A new method for preparation of 4-hydroxy-3-nitro-1,4-dihydrotriazolo[5,1-c][1,2,4]-triazines using 1-nitro-2-morpholinoethylene and 3-diazo-1,2,4-triazoles is proposed. Antiviral activity against the Coxsackie B3 virus and electrochemical transformations of the prepared compounds are studied. © 2022, Springer Science+Business Media LLC.Russian Science Foundation, RSF, (20-13-00142)This work was performed under financial support of the Russian Science Foundation (Project No. 20-13-00142)

Профилактика аденовирусной инфекции в детских дошкольных учреждениях с помощью препарата рекомбинантного интерферона 2b

This article presents the results of experimental (on cell cultures) and clinical (in children’s groups) studies of recombinant interferon alpha-2b medication (Grippferon). Our aim was to examine the virus-inhibitory activity of this medication (against adenovirus) and its preventive effect (on causative agents of ARVI), which allows us to use this medication as a preventive measure against adenovirus (as well as any other) infection in children’s groups.Представлены результаты экспериментального (на клеточных культурах) и клинического (в детских коллективах) изучения способности рекомбинантного интерферона 2b (Гриппферона) оказывать вирусингибирующее (по отношению к аденовирусу) и профилактическое (по отношению к возбудителям ОРВИ) действие, позволяющее использовать данный препарат как средство профилактики аденовирусной (как и любой другой) инфекции в детских коллективах

Synthesis of Pyrimidine Conjugates with 4-(6-Amino-hexanoyl)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine and Evaluation of Their Antiviral Activity

A series of pyrimidine conjugates containing a fragment of racemic 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and its (S)-enantiomer attached via a 6-aminohexanoyl fragment were synthesized by the reaction of nucleophilic substitution of chlorine in various chloropyrimidines. The structures of the synthesized compounds were confirmed by1H,19F, and 13 C NMR spectral data. Enantiomeric purity of optically active derivatives was confirmed by chiral HPLC. Antiviral evaluation of the synthesized compounds has shown that the replacement of purine with a pyrimidine fragment leads to a decrease in the anti-herpesvirus activity compared to the lead compound, purine conjugate. The studied compounds did not exhibit significant activity against influenza A (H1N1) virus. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Russian Science Foundation, RSF: 19-13-00231-PFunding: This research was funded by the Russian Science Foundation, grant number 19-13-00231-P

Bioactive Pyrrolo[2,1-f][1,2,4]triazines: Synthesis, Molecular Docking, In Vitro Cytotoxicity Assay and Antiviral Studies

A series of 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines containing both aryl and thienyl substituents were synthesized by exploiting the 1,3-cycloaddition reaction of N(1)-ethyl-1,2,4-triazinium tetrafluoroborates with dimethyl acetylenedicarboxylate. The antiviral activity of the synthesized compounds against influenza virus strain A/Puerto Rico/8/34 (H1N1) was studied in experiments on Madin-Darby canine kidney (MDCK) cell culture. Among the pyrrolo[2,1-f][1,2,4]triazine derivatives, compounds with low toxicity and high antiviral activity were identified. Dimethyl 4-(4-methoxyphenyl)-7-methyl-2-p-tolylpyrrolo[2,1-f][1,2,4]triazine-5,6-dicarboxylate was found to demonstrate the best antiviral activity (IC50 4 µg/mL and selectivity index 188). Based on the results of in vitro tests and molecular docking studies performed, a plausible mechanism of action for these compounds was suggested to involve inhibition of neuraminidase. © 2023 by the authors.Ministry of Education and Science of the Russian Federation, Minobrnauka: 075-15-2020-777This research was supported by the Ministry of Science and Higher Education of the Russian Federation: Agreement on granting grants from the federal budget in the form of subsidies in accordance with paragraph 4 of Article 78.1 of the Budget Code of the Russian Federation (Moscow, October 1, 2020, No. 075-15-2020-777)

Methods of Synthesis and Antiviral Activity of New 4-Alkyl-3-Nitro-1,4-Dihydroazolo[5,1-c][1,2,4]Triazin-4-ols

[Figure not available: see fulltext.] An azo coupling reaction of α-nitro ketones with 5-diazoazoles was used to obtain 4-alkyl-3-nitro-1,4-dihydroazolo[5,1-с][1,2,4]triazines, which were characterized with respect to their antiviral activity against influenza and Coxsackie B3 viruses. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.This study was funded by the Russian Science Foundation (project No. 20-13-00142)