Biological Significance of a Human Enterovirus B-Specific RNA Element in the 3′ Nontranslated Region

Abstract

The secondary structures predicted for the enteroviral 3 nontranslated region (3NTR) all seem to indicate a conformation consisting of two (X and Y) hairpin structures. The higher-order RNA structure of the 3NTR appears to exist as an intramolecular kissing interaction between the loops of these two hairpin structures. The enterovirus B-like subgroup possesses an additional stem-loop structure, domain Z, which is not present in the poliovirus-like enteroviruses. It has been suggested that the Z domain originated from a burst of short sequence repetitions (E. V. Pilipenko, S. V. Maslova, A. N. Sinyakov, and V. I. Agol, Nucleic Acids Res. 20:1739-1745, 1992). However, no functional features have yet been ascribed to this enterovirus B-like-specific RNA element in the 3NTR. In this study, we tested the functional characteristics and biological significance of domain Z. A mutant of the cardiovirulent coxsackievirus group B3 strain Nancy which completely lacked the Z domain and which therefore acquired enterovirus C-like secondary structures exhibited a wild-type growth phenotype, as determined by single-cycle growth analysis with BGM cells. This result proves that the Z domain is virtually dispensable for viral growth in tissue cultures. Partial distortion of the Z domain structure resulted in a disabled virus with reduced growth kinetics, probably due to alternative conformations of the overall structure of the domain. Infection of mice showed that the recombinant coxsackievirus group B3 mutant which completely lacked the Z domain was less virulent. Pancreatic tissues from mice infected with wild-type virus and recombinant virus were equally affected. However, the heart tissue from mice infected with the recombinant virus showed only slight signs of myocarditis. These results suggest that the enterovirus B-like-specific Z domain plays a role in coxsackievirus-induced pathogenesis.

Breaking pseudo-twofold symmetry in the poliovirus 3'-UTR Y-stem by restoring Watson-Crick base pairs

“…This does not necessarily mean that there is no effect at all, but rather shows the limited use of an in vitro assay to evaluate functional importance. This is not unprecedented, and has been shown before, for instance, in our study of the structural and functional properties of the 39-UTR domain of coxsackievirus B3, an enterovirus closely related to poliovirus (Merkle et al 2002). Poliovirus and coxsackievirus B 39-UTRs share a high similarity in secondary structure, but differ in the presence of an extra, conserved Z-domain in the coxsackievirus B 39-UTR (Rueckert 1996).…”

Molecular characterization of three enteroviral strains isolated in Kuwait from young children with serious conditions

“…Mutations in the EV 5'UTR which plays an important role in the control of replication and translation [25], have been proposed as major determinants of cardiovirulence [26], neurovirulence [23], and myopathogenicity [27]. Similar to the 5′ UTR, the EV 3′ UTR contains secondary structural elements and has been shown to play a role in both translation and replication [28]. It is noteworthy that the secondary structures of both untranslated regions of the 3936 isolate fold at a thermodynamically more favourable free energy level than those of the prototype strain.…”

Synthesis and Biological Evaluation of Novel Benzimidazole Derivatives Bearing a Heterocyclic Ring at 4/5 Position

“…1,2,4-Oxadiazoles (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) were obtained by the treatment of compounds (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) with N-hydroxyacetamidine under EDC/ HOBT conditions. The acid hydrazides (18) was treated with acetic acid in the presence of phosphorus oxychloride afforded 1,3,4-oxadiazoles (31-32).…”

“…Both kinds of proteins were mainly involved in the replication of virus. 28 Due to the special structure of benzimidazole, specific hydrogen bonded interactions could be formed with the genome, interfering the translating process. Therefore, a series of molecules were designed based on the benzimidazole system to inhibit enterovirus.…”

“…General Procedure C: Synthesis of 4/5-(3-Methyl-1,2,4-oxadiazol-5-yl)-2-substituent-1H-benzimidazoles (Compounds [21][22][23][24][25][26][27][28][29][30]. A mixture of appropriate 2-substituent-1H-benzimidazole-4/5-carboxylic acid (1 mmol), EDC·HCl (0.37 g, 2.0 mmol) and HOBt (0.27 g, 2.0 mmol) in DMF or DCM (10 mL) was stirred for 1 h at room temperature.…”