Yellow Fever: Integrating Current Knowledge with Technological Innovations to Identify Strategies for Controlling a Re-Emerging Virus

Kleinert, R.; Montoya-Diaz, Eduardo; Khera, Tanvi; Welsch, Kathrin; Tegtmeyer, Birthe; Hoehl, Sebastian; Ciesek, Sandra; Brown, Richard J. P.

doi:10.3390/v11100960

Cited by 22 publications

(28 citation statements)

References 246 publications

(322 reference statements)

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“…YFV belongs to the genus Flavivirus, which includes the Dengue and Zika viruses. These viruses have a highly conserved NS5 whose interactions, if disrupted, result in the loss of viral replication, likely across all flaviviruses [4,15]. We have previously reported that AT-752 has a direct effect on dengue viral replication, and presumably YFV as well, by forming the intracellular active triphosphate AT-9010, which then inhibits the RdRp responsible for viral replication [12].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, this deadly virus is a threat in regions where the vaccine is under-utilized, resulting in unanticipated cases from outbreaks or emergence in areas that have previously not been affected 4 by the virus, as observed by the recent large outbreaks and YFV emergence in Brazil and several African countries [4,5] that have caused significant morbidity and mortality.…”

Section: Introductionmentioning

confidence: 99%

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AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model

Lin

Good

Julander

et al. 2021

Preprint

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Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing a viral hemorrhagic fever associated with high mortality rates. While an effective vaccine is available, having an effective antiviral against YFV is critical against unexpected outbreaks, or when vaccination is not recommended. We have previously identified AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, as a potent inhibitor of YFV in vitro , with a 50% effective concentration (EC 50 ) of 0.31 µM. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log 10 -fold and serum alanine aminotransferase (ALT) 2-fold compared to sham-infected animals. Treatment with 1000 mg/kg AT-752 for 7 days, initiated 4 h prior to viral challenge, reduced viremia to below the limit of detection by day 4 post infection (pi) and returned ALT to normal levels by day 6 pi. When treatment with AT-752 was initiated 2 days pi, the virus titer and ALT dropped >2 log 10 and 53% by day 4 and 6 pi, respectively. In addition, at 21 days pi, 70 – 100% of the infected animals in the treatment groups survived compared to 0% of the untreated group (p<0.001). Moreover, in vivo formation of the active triphosphate metabolite AT-9010 was measured in the animal tissues, with the highest concentrations in liver and kidney, organs that are vulnerable to the virus. The demonstrated in vivo activity of AT-752 suggests that it is a promising compound for clinical development in the treatment of YFV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model

Lin

Good

Julander

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Yellow fever (YF) is a viral hemorrhagic disease caused by a zoonotic pathogen known as yellow fever virus (YFV) [1]. Yellow fever is considered a mosquito-borne disease that is mostly common in the tropical zones of South America and Africa [2].…”

Section: Introductionmentioning

confidence: 99%

Virtual Screening of FDA Approved Drugs Library to Identify a Potential Inhibitor against NS2B-NS3 Protease of Yellow Fever Virus

Odhar

Ahjel

Albeer

et al. 2021

JPRI

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Yellow fever is a neglected hemorrhagic disease with a high case fatality rate ranging between 25% and 50% for the hospitalized patients. Yellow fever disease is caused by a zoonotic pathogen known as yellow fever virus. This RNA virus is usually transmitted by mosquitos and it is considered endemic in the tropical regions of South America and Africa. Although an effective vaccine is available for yellow fever virus, no antiviral drug is yet licensed against the disease. Thus, yellow fever virus is still representing a re-emerging threat among unvaccinated individuals in endemic regions. The NS2B-NS3 protease seems to play an important role in yellow fever virus replication cycle. As such, the NS2B-NS3 protease may represent a potential target for structure-based drug design and discovery. In this direction, computational approaches like virtual screening can be utilized to hasten the design of novel antivirals and/ or repurposing an already FDA approved drugs. In this in silico study, an FDA approved drugs library was screened against NS2B-NS3 protease crystal of yellow fever virus. Then the best hits with least energy of binding and ability of hydrogen bonding with key residues of protease active site were then selected and submitted to molecular dynamics simulation. And throughout simulation interval, only Olsalazine was able to stay in close proximity to the active site of protease crystal with least average MM-PBSA binding energy as compared to Dantrolene, Belinostat and Linezolid. This indicates that Olsalazine may have the best capacity to bind to NS2B-NS3 protease and interfere with its activity.

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“…Они поражают нервную систему, вызывая парезы, параличи и энцефалиты и, кроме того, часто проявляются симптомами геморрагических лихорадок. Наиболее известны сезонный клещевой энцефалит [6], лихорадка денге [7], желтая лихорадка [8], лихорадка Западного Нила [9] и др. Последнее время в связи с развитием туризма, миграционными процессами и активизацией деловых связей возникла проблема завозных случаев вирусных заболеваний из тропических и субтропических стран в неэндемичные районы, в том числе и в Россию [10,11].…”

Section: Introductionunclassified

Flavivirus Species Recognition Based On the Polyprotein Coding Sequences

Chaley¹,

Tyulko²,

Kutyrkin³

2019

Math.Biol.Bioinf.

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Method recognizing the flavivirus species, including a subtype recognition, that based on the genome sequence analysis, is proposed. This method takes into consideration frequency characteristics of amino acid codons in the coding sequences of full-length polyprotein of flavivirus genomes. High reliability of the method is proved in recognizing flavivirus genomes from 15 groups of different species and sub-types, that are sufficiently represented in the GenBank database. Ten various species of the flaviviruses, four sub-types of Dengue virus and Kunjin virus, that is suggested to be a sub-type of West Nile virus, are considered in the work.

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Yellow Fever: Integrating Current Knowledge with Technological Innovations to Identify Strategies for Controlling a Re-Emerging Virus

Cited by 22 publications

References 246 publications

AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model

AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model

Virtual Screening of FDA Approved Drugs Library to Identify a Potential Inhibitor against NS2B-NS3 Protease of Yellow Fever Virus

Flavivirus Species Recognition Based On the Polyprotein Coding Sequences

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