Structure of Dengue Virus: Implications for Flavivirus Organization, Maturation, and Fusion

Kuhn, Richard J.; Zhang, Wei; Rossmann, Michael G.; Pletnev, Sergei; Corver, Jeroen; Lenches, Edith M.; Jones, Christopher E.; Mukhopadhyay, Suchetana; Chipman, Paul R.; Strauss, Ellen G.; Baker, Timothy S.; Strauss, James H.

doi:10.1142/9789814513357_0037

Cited by 225 publications

(340 citation statements)

References 13 publications

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“…Similar peptides also induce mitochondrial membrane permeability, although the relevance of this to natural infection is unclear (Catteau et al, 2003). Single-TMD topology has also been predicted for M, implying that two membrane-associated forms may exist, potentially as a result of the tight turn (3 aa) between the two TMDs found within particles (Kuhn et al, 2002;Yu et al, 2008;Zhang et al, 2003). Much like Vpu and 6K, investigators are yet to assign a functional role to potential M-mediated channel activity, although mutation of a highly conserved His39 in the first TMD reduced dengue virus spread without affecting polyprotein processing or the formation of prM-E heterodimers, yet this did prevent glycoprotein secretion, which may conceivably relate to channel-forming activity (Pryor et al, 2004).…”

Section: Flavivirus M Proteinmentioning

confidence: 91%

“…The 75 aa small M (membrane) protein is cleaved from the viral E protein by signal peptidase as a prM precursor, which is then processed in the Golgi and acidifying secretory compartments by furinlike proteases into M and the pr peptide (Junjhon et al, 2008;Keelapang et al, 2004;Kuhn et al, 2002;Wong et al, 2012;Yu et al, 2008). The release of virions from the cell surface results in the loss of pr and resultant formation of a mature, infectious virion (Junjhon et al, 2008(Junjhon et al, , 2010Yu et al, 2008Yu et al, , 2009.…”

Section: Flavivirus M Proteinmentioning

confidence: 99%

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Viroporins: structure, function and potential as antiviral targets

Scott

Griffin

2015

Journal of General Virology

120

146

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The channel-forming activity of a family of small, hydrophobic integral membrane proteins termed 'viroporins' is essential to the life cycles of an increasingly diverse range of RNA and DNA viruses, generating significant interest in targeting these proteins for antiviral development. Viroporins vary greatly in terms of their atomic structure and can perform multiple functions during the virus life cycle, including those distinct from their role as oligomeric membrane channels. Recent progress has seen an explosion in both the identification and understanding of many such proteins encoded by highly significant pathogens, yet the prototypic M2 proton channel of influenza A virus remains the only example of a viroporin with provenance as an antiviral drug target. This review attempts to summarize our current understanding of the channel-forming functions for key members of this growing family, including recent progress in structural studies and drug discovery research, as well as novel insights into the life cycles of many viruses revealed by a requirement for viroporin activity. Ultimately, given the successes of drugs targeting ion channels in other areas of medicine, unlocking the therapeutic potential of viroporins represents a valuable goal for many of the most significant viral challenges to human and animal health.

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Section: Flavivirus M Proteinmentioning

confidence: 91%

Section: Flavivirus M Proteinmentioning

confidence: 99%

Viroporins: structure, function and potential as antiviral targets

Scott

Griffin

2015

Journal of General Virology

120

146

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“…Differences in the crystal structures of the BVDV1 and HCV E2 glycoproteins illustrate that common genome arrangement among members of the Flaviviridae family does not translate to structurally similar fusion glycoproteins (29,30). Conversely, structural comparisons indicate that sequences showing marginal homology can display a common class II fold (e.g., dengue virus E and Semliki Forest virus E1 proteins) (37,38). It has been suggested that the use of arthropod vectors may require conservation of the class II fold by distant members of the Togaviridae and Flaviviridae families, while phylogenetically closer viruses that strictly infect mammals may have evolved to develop specialized entry machineries (39).…”

Section: Discussionmentioning

confidence: 99%

Alteration of a Second Putative Fusion Peptide of Structural Glycoprotein E2 of Classical Swine Fever Virus Alters Virus Replication and Virulence in Swine

Holinka

Largo

Gladue

et al. 2016

J Virol

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E2, the major envelope glycoprotein of classical swine fever virus (CSFV), is involved in several critical virus functions, including cell attachment, host range susceptibility, and virulence in natural hosts. Functional structural analysis of E2 based on a WimleyWhite interfacial hydrophobicity distribution predicted the involvement of a loop (residues 864 to 881) stabilized by a disulfide bond ( 869 CKWGGNWTCV 878 , named FPII) in establishing interactions with the host cell membrane. This loop further contains an 872 GG 873 dipeptide, as well as two aromatic residues ( 871 W and 875 W) accessible to solvent. Reverse genetics utilizing a fulllength infectious clone of the highly virulent CSFV strain Brescia (BICv) was used to evaluate how amino acid substitutions within FPII may affect replication of BICv in vitro and virus virulence in swine. Recombinant CSFVs containing mutations in different residues of FPII were constructed. A particular construct, harboring amino acid substitutions W871T, W875D, and V878T (FPII.2), demonstrated a significantly decreased ability to replicate in a swine cell line (SK6) and swine macrophage primary cell cultures. Interestingly, mutated virus FPII.2 was completely attenuated in pigs. Also, animals infected with FPII.2 virus were protected against virulent challenge with Brescia virus at 21 days postvaccination. Supporting a role for the E2 the loop from residues 864 to 881 in membrane fusion, only synthetic peptides that were based on the native E2 functional sequence were competent for insertion into model membranes and perturbation of their integrity, and this functionality was lost in synthetic peptides harboring amino acid substitutions W871T, W875D, and V878T in FPII.2. IMPORTANCEThis report describes the identification and characterization of a putative fusion peptide (FP) in the major structural protein E2 of classical swine fever virus (CSFV). The FP identification was performed by functional structural analysis of E2. We characterized the functional significance of this FP by using artificial membranes. Replacement of critical amino acid residues within the FP radically alters how it interacts with the artificial membranes. When we introduced the same mutations into the viral sequence, there was a reduction in replication in cell cultures, and when we infected domestic swine, the natural host of CSFV host, we observed that the virus was now completely attenuated in swine. In addition, the virus mutant that was attenuated in vivo efficiently protected pigs against wild-type virus. These results provide the proof of principle to support as a strategy for vaccine development the discovery and manipulation of FPs. C lassical swine fever (CSF) is a highly contagious disease of swine caused by CSF virus (CSFV), a small enveloped virus with a positive-sense, single-strand RNA genome (1). The approximately 12.5-kb CSFV genome contains a single open reading frame that encodes a polyprotein composed of 3,898 amino acids that ultimately yields up to 12 final cleavage pr...

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“…It belongs to a family of Flaviviruses (which also includes the Dengue, yellow fever and West Nile viruses), a single stranded, positive-sense RNA virus with a 10.7 Kb genome encoding a single polyprotein that is cleaved into three structural proteins (C, precursor M/M, and E) and seven non-structural [67]. The envelope of Flaviviruses, determined by cryo-electron microscopy, was shown to be made up of 180 copies of two different proteins, the envelope (E) protein and membrane (M) protein, in which 90 E dimers completely cover the viral surface [68,69]. E protein is a glycoprotein responsible for virus entry, representing a major target of neutralizing antibodies for Flaviviruses, including Zika virus, Dengue virus, and other mosquito-transmitted viruses from the same family, was shown to bind to DC-SIGN via the glycans on E proteins of the mature virion [70].…”

Section: Zika Virusmentioning

confidence: 99%

Exploitation of Glycobiology in Anti-Adhesion Approaches against Biothreat Agents

Utratna¹,

Deegan²,

Joshi³

2016

J Bioterror Biodef

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Pathogen adherence to a host cell is one of the first essential steps for establishing invasion, colonization and release of virulence factors such as toxins. Understanding the mechanisms used by pathogens and toxins to adhere and invade human cells could lead to the development of new strategies for preventing and controlling the spread of infectious diseases. This review focuses on carbohydrate-lectin interactions utilized by selected biothreat agents to bind and invade host cells. The principle of using anti-adhesion molecules, based on glycobiology research, has already been shown to be effective in the treatment of influenza. Therefore, translating the same principle to other biothreat agents that mediate invasion of a host cell through carbohydrate-lectin mechanisms is a very promising strategy. We investigate recent literature to highlight the latest developments in the field of glycobiology focused on inhibiting the initial steps of pathogen invasion, with examples for bacteria, toxin and virus interactions. The successful glycomimetics and glycoconjugates represent strategies for interruption of adhesion by single molecules and in multivalent systems against uropathogenic E. coli, several toxins (Shiga-like, cholera, botulinum) and wellknown or emerging viruses (influenza, HIV, Ebola, and Zika). This review provides promising directions and prophylactic as well as therapeutic potential of anti-adhesive strategies against selected biothreat targets.

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Structure of Dengue Virus: Implications for Flavivirus Organization, Maturation, and Fusion

Cited by 225 publications

References 13 publications

Viroporins: structure, function and potential as antiviral targets

Viroporins: structure, function and potential as antiviral targets

Alteration of a Second Putative Fusion Peptide of Structural Glycoprotein E2 of Classical Swine Fever Virus Alters Virus Replication and Virulence in Swine

Exploitation of Glycobiology in Anti-Adhesion Approaches against Biothreat Agents

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