Structural characterization and polymorphism analysis of the NS2B-NS3 protease from the 2017 Brazilian circulating strain of Yellow Fever virus

Noske, G.D.; Gawriljuk, V.O.; Fernandes, R.S.; Furtado, Nathália Dias; Bonaldo, Myrna C.; Oliva, Glaucius; Godoy, Andre S.

doi:10.1016/j.bbagen.2020.129521

Cited by 15 publications

(28 citation statements)

References 55 publications

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“…Although there is a crystallographic structure (PDB id: 1yks) of the helicase domain (37) and another containing part of NS3 complexed with NS2B (PDB id 6urv) (38) deposited in the PDB, the referred SNV occurs in the unresolved stretch. The I184V (NHP dataset) is in the linker region (shown in orange in Figure 4-C , left).…”

Section: Resultsmentioning

confidence: 99%

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Machine learning models exploring characteristic single-nucleotide signatures in Yellow Fever Virus

Salgado¹,

Minardi

Giovanetti

et al. 2021

Preprint

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Yellow fever virus (YFV) is the agent of the most severe mosquito-borne disease in the tropics. Recently, Brazil suffered major YFV outbreaks with a high fatality rate affecting areas where the virus has not been reported for decades, consisting of urban areas where a large number of unvaccinated people live. We developed a machine learning framework combining three different algorithms (XGBoost, random forest and regularized logistic regression). This method was applied to 56 YFV sequences from human infections and 27 from non-human primate (NHPs) infections to investigate the presence of genetic signatures possibly related to disease severity (in human related sequences) and differences in the PCR cycle threshold (Ct) values (in NHP related sequences). Our analyses reveal four non-synonymous single nucleotide variations (SNVs) on sequences from human infections, in proteins NS3 (E614D), NS4a (I69V), NS5 (R727G, V643A) and six non-synonymous SNVs on NHP sequences, in proteins E (L385F), NS1 (A171V), NS3 (I184V) and NS5 (N11S, I374V, E641D). We performed comparative protein structural analysis on these SNVs, describing possible impacts on protein function. Despite the fact that the dataset is limited in size and that this study does not consider virus-host interactions, our work highlights the use of machine learning as a versatile and fast initial approach to genomic data exploration.

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Section: Resultsmentioning

confidence: 99%

“…Although there is a crystallographic structure (PDB id: 1yks) of the helicase domain (37) and another containing part of NS3 complexed with NS2B (PDB id 6urv) (38)…”

Section: Ns3 Proteinmentioning

confidence: 99%

Machine learning models exploring characteristic single-nucleotide signatures in Yellow Fever Virus

Salgado¹,

Minardi

Giovanetti

et al. 2021

Preprint

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“…The His–Asp–Ser catalytic triad between the two barrels ZIKV NS3 is conserved. This catalytic triad could recognize its substrate with high specificity ( Figure 4 b) [ 83 ]. Furthermore, the C-terminal of NS3, as an RNA helicase, can break down double-stranded RNA (dsRNA) to provide a single-stranded RNA (ssRNA) template for the replication of the viral genome, and subsequently mediate the synthesis of the N terminal cap structure by RTPase.…”

Section: The Structures and Functions Of Flavivirus Proteinsmentioning

confidence: 99%

Flavivirus: From Structure to Therapeutics Development

Zhao

Wang

Cao

et al. 2021

Life

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Flaviviruses are still a hidden threat to global human safety, as we are reminded by recent reports of dengue virus infections in Singapore and African-lineage-like Zika virus infections in Brazil. Therapeutic drugs or vaccines for flavivirus infections are in urgent need but are not well developed. The Flaviviridae family comprises a large group of enveloped viruses with a single-strand RNA genome of positive polarity. The genome of flavivirus encodes ten proteins, and each of them plays a different and important role in viral infection. In this review, we briefly summarized the major information of flavivirus and further introduced some strategies for the design and development of vaccines and anti-flavivirus compound drugs based on the structure of the viral proteins. There is no doubt that in the past few years, studies of antiviral drugs have achieved solid progress based on better understanding of the flavivirus biology. However, currently, there are no fully effective antiviral drugs or vaccines for most flaviviruses. We hope that this review may provide useful information for future development of anti-flavivirus drugs and vaccines.

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“…After uploading FDA approved drugs library, these drugs were screened against NS2B-NS3 protease crystal of YFV. This protease crystal, with PDB code of 6URV, was obtained from Protein Data bank [22,23]. For simplicity of screening, only chains A and B of NS2B-NS3 protease crystal were used while other chains were deleted by using USCF chimera version 1.15 [24].…”

Section: Structure-based Virtual Screening (Sbvs)mentioning

confidence: 99%

“…The structural proteins include capsid (C), envelope (E) and membrane (M) proteins and they are important for viral particles formation. While nonstructural proteins (NS) are essential for virus replication machinery, and these proteins namely are NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5 [13]. The amino terminus of NS3 is considered a typical serine protease and it needs NS2B as a cofactor.…”

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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Structural characterization and polymorphism analysis of the NS2B-NS3 protease from the 2017 Brazilian circulating strain of Yellow Fever virus

Cited by 15 publications

References 55 publications

Machine learning models exploring characteristic single-nucleotide signatures in Yellow Fever Virus

Machine learning models exploring characteristic single-nucleotide signatures in Yellow Fever Virus

Flavivirus: From Structure to Therapeutics Development

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

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