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

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

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

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

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)

ОСЕЛЬТАМИВИР — СРЕДСТВО ПРОТИВОВИРУСНОЙ ТЕРАПИИ ГРИППА A(H1N1)pdm09 У ДЕТЕЙ И ВЗРОСЛЫХ

In this article are presented the results of comparative of experimental (on cell cultures) study of the influenza virus strains sensitivity to neuraminidase  inhibitor — Oseltamivir and blocker of M-canal — Rimantadin аnd the results of study effectiveness of the inclusion in the complex therapy of 331 hospitalized patients (children and adults) rapy of А(Н1N1)pdm09 antiviral drug — inhibitor of neuraminidase Oseltamivir that occurred during the epidemic seasons 2009—2010 and 2015—2016  in terms of observational clinical studies.  It is shown that this drug, can be successfully used in the treatment of children and adults with influenza А(Н1N1)pdm09 during 8—9 years after beginning of pandemic cycle.Представлены  результаты сравнительного  исследования чувствительности  вирусов гриппа  к противовирусным препаратам, ингибитору нейраминидазы — осельтамивиру и блокатору М2 канала — римантадину, а также данные изучения лечебной эффективности осельтамивира в терапии 331 пациента (детей и взрослых) с верифицированным  гриппом А(H1N1)pdm/2009, госпитализированных в течение эпидсезонов 2009—2010  и 2015—2016  гг. в условиях наблюдательного клинического исследования. Показано, что препарат может успешно использоваться при лечении детей и взрослых с гриппом А(Н1N1)pdm09 и через 8—9 лет после начала пандемического цикла

Anti-viral activity of enisamium iodide against viruses of influenza and ARVI’s on different cell lines

Influenza and ARVI represent the most numerous and dangerous group of causative agents of respiratory infections human. AIM: Characterization of the antiviral properties of enisamium iodide against human respiratory viruses in in vitro experiments. MATERIALS AND METHODS: In the course of experiments, the cytotoxic properties of enisamium iodide were studied against the cell lines Vero, MA-104, A549, L-41 and HEp-2. The antiviral activity of enisamium iodide was studied using virus yield reduction assay against influenza viruses, parainfluenza virus, respiratory syncytial virus, Coxsackie B3 and Coxsackie B4 viruses, as well as adenoviruses types 5 and 6. RESULTS: The most sensitive to the action of enisamium iodide was the human parainfluenza virus, whose activity decreased by 2.3 orders of magnitude under the action of the drug in A549 cells. Of the cell cultures used, enisamium iodide exhibited the maximum antiviral effect in human lung carcinoma cells A549, where, in its presence, the level of reproduction of adenoviruses of types 5 and 6, Coxsackie viruses B3 and B4, and human parainfluenza virus decreased by an order of magnitude or more. The antiviral activity of enisamium iodide was least manifested in Vero cells. CONCLUSION: According to the results of in vitro experiments, enisamium iodide can be considered as an antiviral drug with a wide spectrum of activity against human respiratory viruses

INFLUENCE ON CELLULAR TARGETS FOR TREATING INFLUENZA INFECTION

Аbstract. Influenza is a highly contagious infection of humans. The use of specific antivirals leads to emergence of drug-resistant strains following by the decrease of efficacy of ethiotropic chemotherapy. In this review the data about the decrease of the level of viral replication and severity of pathological process based on the use of alternative targets of cellular instead of viral origin are presented. The medicines for decreasing the production of proinflammatory cytokines (eritoran), restricting the degranulation of mast cells (ketotifen), inhibitors of cyclooxygenases (celexocib, mesalasine, SC-560), inhibitors of sphingosine-1-phospate pathway (AAL-R) and compounds increasing the capillars stability by strengthe ning the contacts between endothelial cells (Slit protein) have been described in the review. The special attention is paid to the inhibitors of cellular pathways that are used by the virus to provide its reproduction, such as NF-κB, Raf/MEK/ERK, PI3K/AKT/mTOR. Information concerning anti-influenza activity of kinase and autophagy inhibitors is summarised as well as data about the preparations of combined mechanism of activity — glycirrhizic acid and dipeptide alpha-glutamyl-tryptophane. Further studies in the field of search and optimization of inhibitors of cellular components as remedies against influenza infection could lead to the development of novel antivirals with high efficacy, broad spectrum of activity and low probability of virus resistance

Synthesis and Inhibition of Influenza H1N1 Virus by Indolo-Glycyrrhetic Acid Cyanoesters

Two new indolo-glycyrrhetic acid derivatives containing cyano-substitutent at C30 have been synthesized, and their anti-influenza activity has been evaluated in vitro. The resulting data demonstrated moderate inhibitory activity against the H1N1 virus with IC50 29 and 23 μM, respectively. The value of SI 18 and 21 confirm low toxicity and potential of new compounds for following research and development of new biological agents