scholarly journals Dengue virus strain 2 capsid protein switches the annealing pathway and reduces the intrinsic dynamics of the conserved 5’ untranslated region

2020 ◽  
Author(s):  
Xin Ee Yong ◽  
Palur Venkata Raghuvamsi ◽  
Ganesh S. Anand ◽  
Thorsten Wohland ◽  
Kamal K. Sharma

ABSTRACTThe capsid protein of Dengue Virus strain 2 (DENV2C) is a structural protein with RNA chaperone activity that promotes multiple nucleic acid structural rearrangements, critical for transcription of the single-stranded positive-sense DENV2 genomic RNA. Annealing of the conserved 5’ untranslated region (5’UTR) to either its complementary sequence or to the 3’ untranslated region (3’UTR) occurs during (+)/(−) ds-RNA formation and (+) RNA circularization, respectively, both essential steps during DENV RNA replication. We investigated the effect of DENV2C on the annealing mechanism of two hairpin structures from the 5’UTR region (21-nt upstream AUG region (5’UAR) and 23-nt capsid-coding hairpin (5’cHP)) to their complementary sequences during (+)/(−) ds-RNA formation and (+) RNA circularization. Using fluorescence spectroscopy, DENV2C was found to switch annealing reactions nucleated mainly through kissing-loop intermediates to stem-stem interactions during (+)/(−) ds-RNA formation while it promotes annealing mainly through kissing-loop interactions during the (+) RNA circularization. Using FRET-FCS and trFRET, we determined that DENV2C exerts RNA chaperone activities by modulating intrinsic dynamics and by reducing the kinetically trapped unfavorable conformations of the 5’UTR sequence. Thus, DENV2C is likely to facilitate genome folding into functional conformations required for replication, playing a role in modulating (+)/(−) ds-RNA formation and (+) RNA circularization.

RNA Biology ◽  
2021 ◽  
pp. 1-14
Author(s):  
Xin Ee Yong ◽  
Palur Venkata Raghuvamsi ◽  
Ganesh S. Anand ◽  
Thorsten Wohland ◽  
Kamal K. Sharma

2019 ◽  
Vol 20 (16) ◽  
pp. 3870 ◽  
Author(s):  
Faustino ◽  
Martins ◽  
Karguth ◽  
Artilheiro ◽  
Enguita ◽  
...  

Dengue, West Nile and Zika, closely related viruses of the Flaviviridae family, are an increasing global threat, due to the expansion of their mosquito vectors. They present a very similar viral particle with an outer lipid bilayer containing two viral proteins and, within it, the nucleocapsid core. This core is composed by the viral RNA complexed with multiple copies of the capsid protein, a crucial structural protein that mediates not only viral assembly, but also encapsidation, by interacting with host lipid systems. The capsid is a homodimeric protein that contains a disordered N-terminal region, an intermediate flexible fold section and a very stable conserved fold region. Since a better understanding of its structure can give light into its biological activity, here, first, we compared and analyzed relevant mosquito-borne Flavivirus capsid protein sequences and their predicted structures. Then, we studied the alternative conformations enabled by the N-terminal region. Finally, using dengue virus capsid protein as main model, we correlated the protein size, thermal stability and function with its structure/dynamics features. The findings suggest that the capsid protein interaction with host lipid systems leads to minor allosteric changes that may modulate the specific binding of the protein to the viral RNA. Such mechanism can be targeted in future drug development strategies, namely by using improved versions of pep14-23, a dengue virus capsid protein peptide inhibitor, previously developed by us. Such knowledge can yield promising advances against Zika, dengue and closely related Flavivirus.


2016 ◽  
Vol 17 (3) ◽  
pp. 371-380 ◽  
Author(s):  
Qian Xie ◽  
Bao Zhang ◽  
JianHai Yu ◽  
Qinghua Wu ◽  
Fangji Yang ◽  
...  

2021 ◽  
Vol 166 (5) ◽  
pp. 1439-1446 ◽  
Author(s):  
Selvin Noé Palacios-Rápalo ◽  
Luis Adrián De Jesús-González ◽  
José Manuel Reyes-Ruiz ◽  
Juan Fidel Osuna-Ramos ◽  
Carlos Noe Farfan-Morales ◽  
...  

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 726
Author(s):  
Nikole L. Warner ◽  
Kathryn M. Frietze

Dengue virus (DENV) is a major global health problem, with over half of the world’s population at risk of infection. Despite over 60 years of efforts, no licensed vaccine suitable for population-based immunization against DENV is available. Here, we describe efforts to engineer epitope-based vaccines against DENV non-structural protein 1 (NS1). NS1 is present in DENV-infected cells as well as secreted into the blood of infected individuals. NS1 causes disruption of endothelial cell barriers, resulting in plasma leakage and hemorrhage. Immunizing against NS1 could elicit antibodies that block NS1 function and also target NS1-infected cells for antibody-dependent cell cytotoxicity. We identified highly conserved regions of NS1 from all four DENV serotypes. We generated synthetic peptides to these regions and chemically conjugated them to bacteriophage Qβ virus-like particles (VLPs). Mice were immunized two times with the candidate vaccines and sera were tested for the presence of antibodies that bound to the cognate peptide, recombinant NS1 from all four DENV serotypes, and DENV-2-infected cells. We found that two of the candidate vaccines elicited antibodies that bound to recombinant NS1, and one candidate vaccine elicited antibodies that bound to DENV-infected cells. These results show that an epitope-specific vaccine against conserved regions of NS1 could be a promising approach for DENV vaccines or therapeutics to bind circulating NS1 protein.


2013 ◽  
Vol 104 (2) ◽  
pp. 415a
Author(s):  
Filomena A. Carvalho ◽  
Ivo C. Martins ◽  
Fabiana A. Carneiro ◽  
Iranaia Assunção-Miranda ◽  
André F. Faustino ◽  
...  

2017 ◽  
Vol 12 (5) ◽  
pp. 1257-1268 ◽  
Author(s):  
Vera Neves ◽  
Frederico Aires-da-Silva ◽  
Maurício Morais ◽  
Lurdes Gano ◽  
Elisabete Ribeiro ◽  
...  

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