Molecular Insights into the Flavivirus Replication Complex

Elsen, Kaïn van den; Quek, Jun-Ping; Luo, Dahai

doi:10.3390/v13060956

Cited by 45 publications

(31 citation statements)

References 176 publications

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“…Structures of this construct reveal that protease exists in open and closed conformations under different conditions [67,95]. The folding of NS3 is almost identical in both conformations while the C-terminal portion of the NS2B region exhibits various conformations [87]. Structural studies show that proteases of dengue West Nile virus and ZIKV are very similar and adopt a chymotrypsin-like structure with two β-barrels.…”

Section: Structure Of Ns2b-ns3 Proteasementioning

confidence: 98%

“…The NS2B-NS3 complex makes the protease approachable to other cleavage sites, which are in close proximity to cell membranes. The non-structural proteins of the virus form a replication complex on the ER membrane [83][84][85][86][87]. The location of NS2B on the membrane is critical for protease activity, which makes NS3 perform its other functions (important for viral replication).…”

Section: Protease Structure and Dynamicsmentioning

confidence: 99%

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Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

Kang

2021

Biomedicines

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Zika virus (ZIKV)—a member of the Flaviviridae family—is an important human pathogen. Its genome encodes a polyprotein that can be further processed into structural and non-structural proteins. ZIKV protease is an important target for antiviral development due to its role in cleaving the polyprotein to release functional viral proteins. The viral protease is a two-component protein complex formed by NS2B and NS3. Structural studies using different approaches demonstrate that conformational changes exist in the protease. The structures and dynamics of this protease in the absence and presence of inhibitors were explored to provide insights into the inhibitor design. The dynamic nature of residues binding to the enzyme cleavage site might be important for the function of the protease. Due to the charges at the protease cleavage site, it is challenging to develop small-molecule compounds acting as substrate competitors. Developing small-molecule compounds to inhibit protease activity through an allosteric mechanism is a feasible strategy because conformational changes are observed in the protease. Herein, structures and dynamics of ZIKV protease are summarized. The conformational changes of ZIKV protease and other proteases in the same family are discussed. The progress in developing allosteric inhibitors is also described. Understanding the structures and dynamics of the proteases are important for designing potent inhibitors.

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Section: Structure Of Ns2b-ns3 Proteasementioning

confidence: 98%

Section: Protease Structure and Dynamicsmentioning

confidence: 99%

Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

Kang

2021

Biomedicines

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“…The C-terminal end of the NS3 protein has three enzymatic properties: a 5′ RNA-triphosphatase (RTP), a nucleoside triphosphatase (NTPase), and a helicase. NS3 forms a complex with NS5 and assists in replication through the unwinding of viral RNA and dephosphorylation prior to 5′-end capping [ 22 ].…”

Section: Transmission and Replication Cycle Of Dengue Virus Inside Mammalian Cellmentioning

confidence: 99%

Dengue Virus Infection: A Tale of Viral Exploitations and Host Responses

Nanaware

Banerjee

Bagchi

et al. 2021

Viruses

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Dengue is a mosquito-borne viral disease (arboviral) caused by the Dengue virus. It is one of the prominent public health problems in tropical and subtropical regions with no effective vaccines. Every year around 400 million people get infected by the Dengue virus, with a mortality rate of about 20% among the patients with severe dengue. The Dengue virus belongs to the Flaviviridae family, and it is an enveloped virus with positive-sense single-stranded RNA as the genetic material. Studies of the infection cycle of this virus revealed potential host targets important for the virus replication cycle. Here in this review article, we will be discussing different stages of the Dengue virus infection cycle inside mammalian host cells and how host proteins are exploited by the virus in the course of infection as well as how the host counteracts the virus by eliciting different antiviral responses.

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“…The non-structural proteins play roles in viral replication and assembly, host innate immune response antagonism, protein cleavage, and more. Their distinct properties are discussed more in-depth in previous articles [13][14][15]. YFV is thought to attach to cells via glycosaminoglycans, but the specific cell receptors that mediate uptake of the virus are unknown [16].…”

Section: Virologymentioning

confidence: 99%

The Present and Future of Yellow Fever Vaccines

Barrett

2021

Pharmaceuticals

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The disease yellow fever (YF) is prevented by a live-attenuated vaccine, termed 17D, which has been in use since the 1930s. One dose of the vaccine is thought to give lifelong (35+ years) protective immunity, and neutralizing antibodies are the correlate of protection. Despite being a vaccine-preventable disease, YF remains a major public health burden, causing an estimated 109,000 severe infections and 51,000 deaths annually. There are issues of supply and demand for the vaccine, and outbreaks in 2016 and 2018 resulted in fractional dosing of the vaccine to meet demand. The World Health Organization (WHO) has established the “Eliminate Yellow Fever Epidemics” (EYE) initiative to reduce the burden of YF over the next 10 years. As with most vaccines, the WHO has recommendations to assure the quality, safety, and efficacy of the YF vaccine. These require the use of live 17D vaccine only produced in embryonated chicken eggs, and safety evaluated in non-human primates only. Thus, any second-generation vaccines would require modification of WHO recommendations if they were to be used in endemic countries. There are multiple second-generation YF vaccine candidates in various stages of development that must be shown to be non-inferior to the current 17D vaccine in terms of safety and immunogenicity to progress through clinical trials to potential licensing. The historic 17D vaccine continues to shape the global vaccine landscape in its use in the generation of multiple licensed recombinant chimeric live vaccines and vaccine candidates, in which its structural protein genes are replaced with those of other viruses, such as dengue and Japanese encephalitis. There is no doubt that the YF 17D live-attenuated vaccine will continue to play a role in the development of new vaccines for YF, as well as potentially for many other pathogens.

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Molecular Insights into the Flavivirus Replication Complex

Cited by 45 publications

References 176 publications

Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

Dengue Virus Infection: A Tale of Viral Exploitations and Host Responses

The Present and Future of Yellow Fever Vaccines

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