Small molecules against viruses causing hemorrhagic fevers in Russia

Osolodkin D.I., Kozlovskaya L.I., Iusupov I.R., Kurkin A.V., Shustova E.Y., Orlov A.A., Khvatov E.V., Mutnykh E.S., Kurashova S.S., Vetrova A.N., Yatsenko D.O., Goryashchenko A.S., Ivanov V.N., Lukyanenko E.R., Karpova E.V., et. al.

AbstractEvolutionary potential of viruses can result in outbreaks of well‐known viruses and emergence of novel ones. Pharmacological methods of intervening the reproduction of various less popular, but not less important viruses are not available, as well as the spectrum of antiviral activity for most known compounds. In the framework of chemical biology paradigm, characterization of antiviral activity spectrum of new compounds allows to extend the antiviral chemical space and provides new important structure–activity relationships for data‐driven drug discovery. Here we present a primary assessment of antiviral activity of spiro‐annulated derivatives of seven‐membered heterocycles, oxepane and azepane, in phenotypic assays against viruses with different genomes, virion structures, and genome realization schemes: orthoflavivirus (tick‐borne encephalitis virus, TBEV), enteroviruses (poliovirus, enterovirus A71, echovirus 30), adenovirus (human adenovirus C5), hantavirus (Puumala virus). Hit compounds inhibited reproduction of adenovirus C5, the only DNA virus in the studied set, in the yield reduction assay, and did not inhibit reproduction of RNA viruses.

Zhdanov K.V., Mal’cev O.V., Kozlov K.V., Miklush P.I., Peredel’skij E.V., Sidorchuk S.N., Kravchuk Y.A., Sigidaev A.S., Dedkov V.G., Konushkaliev A.A.

Crimean haemorrhagic fever (Crimean-Congo haemorrhagic fever) – an important public health problem due to the wide geographical spread, the ability to cause epidemic outbreaks of disease and high mortality. Evidence that human infection in some cases may occur in direct contact with the patient (bypassing the vector) indicates a high risk of contamination of surrounding people. This article presents a case of severe Crimean haemorrhagic fever in combination with tick-borne borreliosis with different clinical manifestations of the disease with many complications developed due to both direct and indirect effects of virus not only on blood cells, the system of hemostasis and vascular component with the development of hemorrhagic syndrome, but also on many organs and systems of the body. The possibility of long-term persistence of the Crimean haemorrhagic fever virus in the human body against the background of the inhibition of the immune system of the body and the severe course of the disease associated with the development of life-threatening complications, leads to a high risk of death, prolonged restorative treatment and extended hospitalization.

Hawman D.W., Feldmann H.

Crimean–Congo haemorrhagic fever (CCHF) is a severe tick-borne illness with a wide geographical distribution and case fatality rates of 30% or higher. Caused by infection with the CCHF virus (CCHFV), cases are reported throughout Africa, the Middle East, Asia and southern and eastern Europe. The expanding range of the Hyalomma tick vector is placing new populations at risk for CCHF, and no licensed vaccines or specific antivirals exist to treat CCHF. Furthermore, despite cases of CCHF being reported annually, the host and viral determinants of CCHFV pathogenesis are poorly understood. CCHFV can productively infect a multitude of animal species, yet only humans develop a severe illness. Within human populations, subclinical infections are underappreciated and may represent a substantial proportion of clinical outcomes. Compared with other members of the Bunyavirales order, CCHFV has a more complex genomic organization, with many viral proteins having unclear functions in viral pathogenesis. In recent years, improved animal models have led to increased insights into CCHFV pathogenesis, and several antivirals and vaccines for CCHFV have shown robust efficacy in preclinical models. Translation of these insights and candidate therapeutics to the clinic will hopefully reduce the morbidity and mortality caused by CCHFV. Crimean–Congo haemorrhagic fever (CCHF) is a severe and often lethal tick-borne illness that is caused by infection with the CCHF virus (CCHFV). In this Review, Hawman and Feldmann explore recent insights into the function of viral proteins in CCHFV pathogenesis, our current understanding of CCHF and the state of treatments and vaccines for CCHFV.

Yarovaya Olga I., Laev Sergey S., Salakhutdinov Nariman F.

The review focuses on low-molecular-weight natural metabolites of the diterpene series and their semi-synthetic analogues, which exhibit antiviral activity. Data on the antiviral activity of both plant extracts and their components are provided. The structures of biologically active natural diterpenoids and their derivatives with a pronounced antiviral effect are presented. Mechanisms of therapeutic action of diterpenoids and their derivatives with a pronounced antiviral effect are considered for different viruses. The review summarizes the data over the last 12 years (2011–2022).The bibliography includes 183 references.

Chupakhin O.N., Rusinov V.L., Varaksin M.V., Ulomskiy E.N., Savateev K.V., Butorin I.I., Du W., Sun Z., Charushin V.N.

This review outlines the data of numerous studies relating to the broad-spectrum antiviral drug Triazavirin that was launched on the Russian pharmaceutical market in 2014 as an anti-influenza drug (the international non-patented name is Riamilovir). The range of antiviral activity of Triazavirin has been significantly expanded during recent years; in particular, it has been shown that Triazavirin exhibits activity against tick-borne encephalitis, Rift Valley fever, West Nile fever, and other infections of viral etiology. This drug has been approved for treatment of influenza and acute respiratory infections by the Russian Ministry of Health on the basis of comprehensive clinical trials involving over 450 patients. Triazavirin was found to be a highly effective and well-tolerated drug, allowing its over-the-counter sale. The recently published data on the use of Triazavirin in clinical practice for the treatment of patients with COVID-19 are discussed, with special attention paid to potential biological targets for this drug.

Belhadi D., El Baied M., Mulier G., Malvy D., Mentré F., Laouénan C.

Background Viral hemorrhagic fevers (VHFs) are a group of diseases, which can be endemo-epidemic in some areas of the world. Most of them are characterized by outbreaks, which occur irregularly and are hard to predict. Innovative medical countermeasures are to be evaluated but due to the field specificities of emerging VHF, challenges arise when implementing clinical studies. To assess the state of the art around VHFs, we conducted a systematic review for all reports and clinical studies that included specific results on number of cases, mortality and treatment of VHFs. Methods The search was conducted in January 2020 based on PRISMA guidelines (PROSPERO CRD42020167306). We searched reports on the WHO and CDC websites, and publications in three international databases (MEDLINE, Embase and CENTRAL). Following the study selection process, qualitative and quantitative data were extracted from each included study. A narrative synthesis approach by each VHF was used. Descriptive statistics were conducted including world maps of cases number and case fatality rates (CFR); summary tables by VHF, country, time period and treatment studies. Results We identified 141 WHO/CDC reports and 126 articles meeting the inclusion criteria. Most of the studies were published after 2010 (n = 97 for WHO/CDC reports and n = 93 for publications) and reported number of cases and/or CFRs (n = 141 WHO/CDC reports and n = 88 publications). Results varied greatly depending on the outbreak or cluster and across countries within each VHF. A total of 90 studies focused on Ebola virus disease (EVD). EVD outbreaks were reported in Africa, where Sierra Leone (14,124 cases; CFR = 28%) and Liberia (10,678 cases; CFR = 45%) reported the highest cases numbers, mainly due to the 2014–2016 western Africa outbreak. Crimean-Congo hemorrhagic fever (CCHF) outbreaks were reported from 31 studies in Africa, Asia and Europe, where Turkey reported the highest cases number (6,538 cases; CFR = 5%) and Afghanistan the last outbreak in 2016/18 (293 cases; CFR = 43%). Regarding the 38 studies reporting results on treatments, most of them were non-randomized studies (mainly retrospective or non-randomized comparative studies), and only 10 studies were randomized controlled trials. For several VHFs, no specific investigational therapeutic option with strong proof of effectiveness on mortality was identified. Conclusion We observed that number of cases and CFR varied greatly across VHFs as well as across countries within each VHF. The number of studies on VHF treatments was very limited with very few randomized trials and no strong proof of effectiveness of treatment against most of the VHFs. Therefore, there is a high need of methodologically strong clinical trials conducted in the context of VHF.

Flórez-Álvarez L., de Souza E.E., Botosso V.F., de Oliveira D.B., Ho P.L., Taborda C.P., Palmisano G., Capurro M.L., Pinho J.R., Ferreira H.L., Minoprio P., Arruda E., de Souza Ferreira L.C., Wrenger C., Durigon E.L.

Hemorrhagic fever viruses (HFVs) pose a threat to global public health owing to the emergence and re-emergence of highly fatal diseases. Viral hemorrhagic fevers (VHFs) caused by these viruses are mostly characterized by an acute febrile syndrome with coagulation abnormalities and generalized hemorrhage that may lead to life-threatening organ dysfunction. Currently, the events underlying the viral pathogenicity associated with multiple organ dysfunction syndrome still underexplored. In this minireview, we address the current knowledge of the mechanisms underlying VHFs pathogenesis and discuss the available development of preventive and therapeutic options to treat these infections. Furthermore, we discuss the potential of HFVs to cause worldwide emergencies along with factors that favor their spread beyond their original niches.

Jiang H., Huang C., Bai X., Zhang F., Lin B., Wang S., Jia Z., Wang J., Liu J., Dang S., Zhao Y., Dou X., Cui F., Zhang W., Lian J., et. al.

López-López E., Fernández-de Gortari E., Medina-Franco J.L.

In analogy with structure-activity relationships (SARs), which are at the core of medicinal chemistry, studying structure-inactivity relationships (SIRs) is essential to understanding and predicting biological activity. Current computational methods should predict or distinguish 'activity' and 'inactivity' with the same confidence because both concepts are complementary. However, the lack of inactivity data, in particular in the public domain, limits the development of predictive models and its broad application. In this review, we encourage the scientific community to disclose and analyze high-confidence activity data considering both the labeled 'active' and 'inactive' compounds.

Wagner E., Shin A., Tukhanova N., Turebekov N., Nurmakhanov T., Sutyagin V., Berdibekov A., Maikanov N., Lezdinsh I., Shapiyeva Z., Shevtsov A., Freimüller K., Peintner L., Ehrhardt C., Essbauer S.

Omsk haemorrhagic fever virus (OHFV) is the agent leading to Omsk haemorrhagic fever (OHF), a viral disease currently only known in Western Siberia in Russia. The symptoms include fever, headache, nausea, muscle pain, cough and haemorrhages. The transmission cycle of OHFV is complex. Tick bites or contact with infected small mammals are the main source of infection. The Republic of Kazakhstan is adjacent to the endemic areas of OHFV in Russia and febrile diseases with haemorrhages occur throughout the country—often with unclear aetiology. In this study, we examined human cerebrospinal fluid samples of patients with suspected meningitis or meningoencephalitis with unknown origins for the presence of OHFV RNA. Further, reservoir hosts such as rodents and ticks from four Kazakhstan regions were screened for OHFV RNA to clarify if this virus could be the causative agent for many undiagnosed cases of febrile diseases in humans in Kazakhstan. Out of 130 cerebrospinal fluid samples, two patients (1.53%) originating from Almaty city were positive for OHFV RNA. Screening of tick samples revealed positive pools from different areas in the Akmola region. Of the caught rodents, 1.1% out of 621 were positive for OHFV at four trapping areas from the West Kazakhstan region. In this paper, we present a broad investigation of the spread of OHFV in Kazakhstan in human cerebrospinal fluid samples, rodents and ticks. Our study shows for the first time that OHFV can not only be found in the area of Western Siberia in Russia, but can also be detected up to 1.600 km away in the Almaty region in patients and natural foci.

Hirano M., Sakurai Y., Urata S., Kurosaki Y., Yasuda J., Yoshii K.

Crimean-Congo hemorrhagic fever virus (CCHFV) belongs to the genus Orthonairovirus and is the causative agent of a viral hemorrhagic disease with a case fatality rate of 30%. However, limited studies have been conducted to explore antiviral compounds specific to CCHFV. In this study, we developed a minigenome system of orthonairoviruses, CCHFV and Hazara virus to analyze viral replication and screened an FDA-approved compound library. The transfection of the minigenome components induced marked increase in luciferase expression, indicating the sufficient replication and translation of reporter RNA. Compound library screening identified 14 candidate compounds that significantly decreased luciferase activity. Some of the compounds also inhibited the replication of the infectious Hazara virus. The mechanism of inhibition by tigecycline was further analyzed, and a decrease in the interaction between the viral N protein and RNA by tigecycline was observed. This work provides a basis for validation using animal models and the design of chemical derivatives with stronger activity in future studies on the development of an antiviral against CCHFV.

Wang Q., Cao R., Li L., Liu J., Yang J., Li W., Yan L., Wang Y., Yan Y., Li J., Deng F., Zhou Y., Wang M., Zhong W., Hu Z.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus that causes fever, hemorrhage, and multi-organ failure, with an average fatality rate of ∼40% in humans. Currently, there are no available vaccines or drugs for the treatment of Crimean-Congo hemorrhagic fever (CCHF). Favipiravir (T-705), a nucleoside analog, protects against CCHFV infection in animal models. Here, we evaluated the anti-CCHFV efficacy of several nucleoside analogs, including some well-known compounds such as remdesivir (GS-5734), EIDD-1931 and its prodrug molnupiravir (EIDD-2801), as well as a novel T-705-derived compound H44. T-705, H44, and EIDD-1931 inhibited CCHFV infection in vitro while GS-5734 had no inhibitory effect. All three nucleoside analogs functioned at the "post-entry" stage of virus infection. However, EIDD-2801 failed to protect type I interferon receptor knockout (IFNAR)-/- mice from CCHFV infection. H44, similar to T-705, conferred 100% protection to IFNAR-/- mice against lethal CCHFV challenge, even with delayed administration. This study provided in vitro and in vivo data regarding the anti-CCHFV efficacy of different nucleosides and identified a novel compound, H44, as a promising drug candidate for the treatment of CCHFV infection in vivo.

Yarovaya O., Zaykovskaya A., Kovaleva K., Pyankov O., Salakhutdinov N.

We have developed a cytopathic model using an MTT test for viruses Hantaan 76-118 and for Puumala 967. Our research has shown that ribavirin is not active with the viruses under study, while being fairly toxic to CC50 20 µM. Triazavirin was active for Hantaan 76-118 in a dose of IC50 14±3 µM, and for Puumala 967 IC50 12±3 µM. The toxicity of Triazavirin was 368±18 µM. The selectivity indices of SI of this agent with regard to these viruses were 26 and 30, respectively.

Mariappan V., Pratheesh P., Shanmugam L., Rao S.R., Pillai A.B.

Viral Hemorrhagic Fever (VHF) is a group of acute zoonotic diseases with high mortality rates caused by seven different families of viruses that infect both humans and animals. VHF is characterized by hemorrhagic manifestations and lethal platelet dysfunction, if not treated properly. Most of the VHF is transmitted to humans by different types of vectors like rodents, bats, ticks, voles, and mosquitoes. Some of the common and deadly VHF are associated with infections like Dengue, Ebola, Yellow Fever, and Hantavirus. These diseases are endemic in a certain part of the world and sometimes cause major outbreaks. Emerging and re-emerging VHF's remain a great health concern across the world due to poor prognosis and lack of specific vaccines or drugs for effective treatment. Understanding the disease pathogenesis of VHF could provide effective means for treating and monitoring the disease outcome. In this regard, the present review gives a brief overview of disease background, molecular pathogenesis of major VHF, and gaps in the understanding of disease mechanism and current trends in disease management. Possible mechanism for thrombocytopenia and vascular leakage in VHFs. • Overview of molecular pathogenesis of Viral Hemorrhagic Fever causing viruses. • The current status of various diagnostics approaches of VHFs at the clinical practices. • Current treatments methods and disease management for VHFs. • Animal Models for Viral Hemorrhagic Fever.

Mayor J., Engler O., Rothenberger S.

Ecological changes, population movements and increasing urbanization promote the expansion of hantaviruses, placing humans at high risk of virus transmission and consequent diseases. The currently limited therapeutic options make the development of antiviral strategies an urgent need. Ribavirin is the only antiviral used currently to treat hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus (HTNV), even though severe side effects are associated with this drug. We therefore investigated the antiviral activity of favipiravir, a new antiviral agent against RNA viruses. Both ribavirin and favipiravir demonstrated similar potent antiviral activity on HTNV infection. When combined, the efficacy of ribavirin is enhanced through the addition of low dose favipiravir, highlighting the possibility to provide better treatment than is currently available.

Diani E., Cecchetto R., Tonon E., Mantoan M., Lotti V., Lagni A., Palmisano A., Piccaluga P.P., Gibellini D.

Omsk hemorrhagic fever virus (OHFV) is the etiological agent of a poorly studied acute viral disease, causing several epidemic waves observed in the western Siberia regions of Omsk, Kurgan, Novosibirsk, and Tyumen. OHFV is a flavivirus and shares structural and morphological features with tick-borne encephalitis (TBE) complex viruses. The disease’s symptoms show high variability, from flu-like symptoms, hyperesthesia, and petechial rush in the upper body to high fever and hemorrhagic manifestations, with a fatality rate of about 1%. The real number of OHFV-infected people is still unknown due to the difficulties in diagnosis and the presence of asymptomatic patients that lead to an underestimation of the total cases. Little is known about the viral infection dynamics at the molecular and cellular levels, the viral involvement in immune escape, cellular pathways alteration, or metabolic influence. It is noteworthy that no clinical trials have currently been performed for effective and specific drug treatments. In this review, we will give an overview of OHFV interactions with humans and animals, diagnostic tools, and drug treatments. We aim to highlight the importance of a frequently undiagnosed or misdiagnosed viral infection that might also even cause severe clinical manifestations such as meningitis and hemorrhage, in order to point out the need to develop new research studies, new diagnostic tools, and new treatments for OHFV.