scholarly journals Antiviral Efficacy of Ribavirin and Favipiravir against Hantaan Virus

2021 ◽  
Vol 9 (6) ◽  
pp. 1306
Author(s):  
Jennifer Mayor ◽  
Olivier Engler ◽  
Sylvia Rothenberger
Keyword(s):  
High Risk ◽  
Antiviral Activity ◽  
Low Dose ◽  
Rna Viruses ◽  
Virus Transmission ◽  
Antiviral Agent ◽  
Hemorrhagic Fever ◽  
Hantaan Virus ◽  
Population Movements ◽  
Ecological Changes

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.

scholarly journals Efficient incorporation and template-dependent polymerase inhibition are major determinants for the broad-spectrum antiviral activity of remdesivir

2021 ◽  
Author(s):  
Matthias Götte ◽  
Calvin J. Gordon ◽  
Hery W. Lee ◽  
Egor P. Tchesnokov ◽  
Jason K. Perry ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Cyano Group ◽  
Nipah Virus ◽  
Antiviral Agent ◽  
Hemorrhagic Fever ◽  
Inhibitory Effects ◽  
Hemorrhagic Fever Virus ◽  
Negative Sense

Remdesivir (RDV) is a direct antiviral agent that is approved in several countries for the treatment of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RDV exhibits broad-spectrum antiviral activity against positive-sense RNA viruses, e.g., SARS-CoV-2 and hepatitis C virus (HCV) and non-segmented negative-sense RNA viruses, e.g., Nipah virus (NiV), while several segmented negative-sense RNA viruses such as influenza (Flu) virus or Crimean-Congo hemorrhagic fever virus (CCHFV) are not sensitive to the drug. The reasons for this apparent pattern are unknown. Here, we expressed and purified representative RNA-dependent RNA polymerases (RdRp) and studied three biochemical parameters that have been associated with the inhibitory effects of RDV-triphosphate (TP): (i) selective incorporation of the nucleotide substrate RDV-TP, (ii) the effect of the incorporated RDV-monophosphate (MP) on primer extension, and (iii) the effect of RDV-MP in the template during incorporation of the complementary UTP. The results of this study revealed a strong correlation between antiviral effects and efficient incorporation of RDV-TP. Delayed chain-termination is heterogeneous and usually inefficient at higher NTP concentrations. In contrast, template-dependent inhibition of UTP incorporation opposite the embedded RDV-MP is seen with all polymerases. Molecular modeling suggests a steric conflict between the 1′-cyano group of RDV-MP and conserved residues of RdRp motif F. We conclude that future efforts in the development of nucleotide analogues with a broader spectrum of antiviral activities should focus on improving rates of incorporation while capitalizing on the inhibitory effects of a bulky 1′-modification.

scholarly journals Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses

2016 ◽  
Vol 126 ◽  
pp. 62-68 ◽  
Author(s):  
Jonna B. Westover ◽  
Eric J. Sefing ◽  
Kevin W. Bailey ◽  
Arnaud J. Van Wettere ◽  
Kie-Hoon Jung ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Low Dose ◽  
Hemorrhagic Fever

scholarly journals Urbanization prolongs hantavirus epidemics in cities

2018 ◽  
Vol 115 (18) ◽  
pp. 4707-4712 ◽  
Author(s):  
Huaiyu Tian ◽  
Shixiong Hu ◽  
Bernard Cazelles ◽  
Gerardo Chowell ◽  
Lidong Gao ◽  
...  
Keyword(s):  
Economic Growth ◽  
Disease Burden ◽  
Communicable Disease ◽  
Disease Outbreaks ◽  
Hemorrhagic Fever ◽  
Current Control ◽  
Hantaan Virus ◽  
Urban Migration ◽  
Population Movements ◽  
Spatiotemporal Analyses

Urbanization and rural–urban migration are two factors driving global patterns of disease and mortality. There is significant concern about their potential impact on disease burden and the effectiveness of current control approaches. Few attempts have been made to increase our understanding of the relationship between urbanization and disease dynamics, although it is generally believed that urban living has contributed to reductions in communicable disease burden in industrialized countries. To investigate this relationship, we carried out spatiotemporal analyses using a 48-year-long dataset of hemorrhagic fever with renal syndrome incidence (HFRS; mainly caused by two serotypes of hantavirus in China: Hantaan virus and Seoul virus) and population movements in an important endemic area of south China during the period 1963–2010. Our findings indicate that epidemics coincide with urbanization, geographic expansion, and migrant movement over time. We found a biphasic inverted U-shaped relationship between HFRS incidence and urbanization, with various endemic turning points associated with economic growth rates in cities. Our results revealed the interrelatedness of urbanization, migration, and hantavirus epidemiology, potentially explaining why urbanizing cities with high economic growth exhibit extended epidemics. Our results also highlight contrasting effects of urbanization on zoonotic disease outbreaks during periods of economic development in China.

scholarly journals T-705 (Favipiravir) Inhibition of Arenavirus Replication in Cell Culture

2010 ◽  
Vol 55 (2) ◽  
pp. 782-787 ◽  
Author(s):  
Michelle Mendenhall ◽  
Andrew Russell ◽  
Terry Juelich ◽  
Emily L. Messina ◽  
Donald F. Smee ◽  
...  
Keyword(s):  
Cell Culture ◽  
Antiviral Activity ◽  
Viral Replication ◽  
Antiviral Agent ◽  
Febrile Illness ◽  
Hemorrhagic Fever ◽  
Intermediate Stage ◽  
Lymphocytic Choriomeningitis ◽  
Hamster Model ◽  
Highly Pathogenic

ABSTRACTA number of New World arenaviruses (Junín [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.

scholarly journals Understanding the Mechanism of the Broad-Spectrum Antiviral Activity of Favipiravir (T-705): Key Role of the F1 Motif of the Viral Polymerase

2017 ◽  
Vol 91 (12) ◽  
Author(s):  
Rana Abdelnabi ◽  
Ana Theresa Silveira de Morais ◽  
Pieter Leyssen ◽  
Isabelle Imbert ◽  
Stéphanie Beaucourt ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Negative Impact ◽  
Antiviral Agent ◽  
Wild Type Virus ◽  
Viral Polymerase ◽  
Ssrna Virus ◽  
Positive Sense

ABSTRACT Favipiravir (T-705) is a broad-spectrum antiviral agent that has been approved in Japan for the treatment of influenza virus infections. T-705 also inhibits the replication of various RNA viruses, including chikungunya virus (CHIKV). We demonstrated earlier that the K291R mutation in the F1 motif of the RNA-dependent RNA polymerase (RdRp) of CHIKV is responsible for low-level resistance to T-705. Interestingly, this lysine is highly conserved in the RdRp of positive-sense single-stranded RNA (+ssRNA) viruses. To obtain insights into the unique broad-spectrum antiviral activity of T-705, we explored the role of this lysine using another +ssRNA virus, namely, coxsackievirus B3 (CVB3). Introduction of the corresponding K-to-R substitution in the CVB3 RdRp (K159R) resulted in a nonviable virus. Replication competence of the K159R variant was restored by spontaneous acquisition of an A239G substitution in the RdRp. A mutagenesis analysis at position K159 identified the K159M variant as the only other viable variant which had also acquired the A239G substitution. The K159 substitutions markedly decreased the processivity of the purified viral RdRp, which was restored by the introduction of the A239G mutation. The K159R A239G and K159M A239G variants proved, surprisingly, more susceptible than the wild-type virus to T-705 and exhibited lower fidelity in polymerase assays. Furthermore, the K159R A239G variant was found to be highly attenuated in mice. We thus demonstrate that the conserved lysine in the F1 motif of the RdRp of +ssRNA viruses is involved in the broad-spectrum antiviral activity of T-705 and that it is a key amino acid for the proper functioning of the enzyme. IMPORTANCE In this study, we report the key role of a highly conserved lysine residue of the viral polymerase in the broad-spectrum antiviral activity of favipiravir (T-705) against positive-sense single-stranded RNA viruses. Substitutions of this conserved lysine have a major negative impact on the functionality of the RdRp. Furthermore, we show that this lysine is involved in the fidelity of the RdRp and that the RdRp fidelity influences the sensitivity of the virus for the antiviral efficacy of T-705. Consequently, these results provide insights into the mechanism of the antiviral activity of T-705 and may lay the basis for the design of novel chemical scaffolds that may be endowed with a more potent broad-spectrum antiviral activity than that of T-705.

scholarly journals Genomic Epidemiology and Active Surveillance to Investigate Outbreaks of Hantaviruses

2021 ◽  
Vol 10 ◽  
Author(s):  
Won-Keun Kim ◽  
Seungchan Cho ◽  
Seung-Ho Lee ◽  
Jin Sun No ◽  
Geum-Young Lee ◽  
...  
Keyword(s):  
Active Surveillance ◽  
Rna Viruses ◽  
Hemorrhagic Fever ◽  
Hantaan Virus ◽  
Genome Sequences ◽  
Viral Genomes ◽  
Genomic Epidemiology ◽  
Significant Public Health ◽  
Infection Source ◽  
Emerging Virus

Emerging and re-emerging RNA viruses pose significant public health, economic, and societal burdens. Hantaviruses (genus Orthohantavirus, family Hantaviridae, order Bunyavirales) are enveloped, negative-sense, single-stranded, tripartite RNA viruses that are emerging zoonotic pathogens harbored by small mammals such as rodents, bats, moles, and shrews. Orthohantavirus infections cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome in humans (HCPS). Active targeted surveillance has elucidated high-resolution phylogeographic relationships between patient- and rodent-derived orthohantavirus genome sequences and identified the infection source by temporally and spatially tracking viral genomes. Active surveillance of patients with HFRS entails 1) recovering whole-genome sequences of Hantaan virus (HTNV) using amplicon (multiplex PCR-based) next-generation sequencing, 2) tracing the putative infection site of a patient by administering an epidemiological questionnaire, and 3) collecting HTNV-positive rodents using targeted rodent trapping. Moreover, viral genome tracking has been recently performed to rapidly and precisely characterize an outbreak from the emerging virus. Here, we reviewed genomic epidemiological and active surveillance data for determining the emergence of zoonotic RNA viruses based on viral genomic sequences obtained from patients and natural reservoirs. This review highlights the recent studies on tracking viral genomes for identifying and characterizing emerging viral outbreaks worldwide. We believe that active surveillance is an effective method for identifying rodent-borne orthohantavirus infection sites, and this report provides insights into disease mitigation and preparedness for managing emerging viral outbreaks.

LOW-DOSE-RATE OR HIGH-DOSE-RATE BRACHYTHERAPY IN COMBINATION WITH EXTERNAL BEAM RADIOTHERAPY FOR INTERMEDIATE AND HIGH-RISK PROSTATE CANCER

2018 ◽  
Vol 64 (1) ◽  
pp. 79-83
Author(s):  
Vladimir Solodkiy ◽  
Andrey Pavlov ◽  
Aleksey Tsybulskiy ◽  
Anton Ivashin
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Dose Rate ◽  
Low Dose ◽  
External Beam Radiotherapy ◽  
Combined Treatment ◽  
High Dose ◽  
External Beam ◽  
Low Dose Rate ◽  
Risk Of Progression

Introduction. One of the main problems of modem on-courology is treatment for prostate cancer of intermediate and high risk of progression. Modern radiotherapy in this category of patients has an advantage over surgical methods of treatment. One way to improve the effectiveness of radiotherapy is to escalate the dose in the prostate gland. For this purpose a combination of brachytherapy and remote radiotherapy is used. This combination allows increasing the dose of radiation, thereby providing better local control, reducing complications from neighboring organs. Purpose of the study. To conduct a comparative analysis of efficacy and safety of radical treatment of patients with prostate cancer at medium and high risk of progression using a combination of high and low dose rate brachytherapy with external beam radiotherapy. Materials and methods. 107 patients with prostate cancer of the group of medium and high risk of progression combined treatment (brachytherapy with external beam radiotherapy) was conducted. 53 patients underwent combined treatment (HDR-brachytherapy and external beam radiotherapy). 54 patients underwent combined treatment (LDR-brachytherapy and external beam radiotherapy). The observation period was 5 years. Conclusion. In a comparative analysis in groups of combined radiotherapy with the use of high-dose and low-dose-rate brachytherapy, the same effectiveness of immediate and long-term results of treatment was demonstrated. A significant reduction in early and late toxic reactions in patients with high-power brachytherapy has been demonstrated.

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