Δημοσίευση

Ultradeep pyrosequencing and molecular modeling identify key structural features of hepatitis B virus RNase H, a putative target for antiviral intervention.

ΤίτλοςUltradeep pyrosequencing and molecular modeling identify key structural features of hepatitis B virus RNase H, a putative target for antiviral intervention.
Publication TypeJournal Article
Year of Publication2014
AuthorsHayer, J., Rodriguez C., Germanidis G., Deléage G., Zoulim F., Pawlotsky J-M., & Combet C.
JournalJ Virol
Volume88
Issue1
Pagination574-82
Date Published2014 Jan
ISSN1098-5514
Λέξεις κλειδιάAmino Acid Sequence, Antiviral Agents, Genotype, Hepatitis B virus, High-Throughput Nucleotide Sequencing, Models, Molecular, Molecular Sequence Data, Ribonuclease H, Sequence Homology, Amino Acid
Abstract

Last-generation nucleoside/nucleotide analogues are potent against hepatitis B virus (HBV) and have a high barrier to resistance. However, delayed responses have been observed in patients previously exposed to other drugs of the same class, long-term resistance is possible, and cure of infection cannot be achieved with these therapies, emphasizing the need for alternative therapeutic approaches. The HBV RNase H represents an interesting target because its enzyme activity is essential to the HBV life cycle. The goal of our study was to characterize the structure of the HBV RNase H by computing a 3-dimensional molecular model derived from E. coli RNase H and analyzing 2,326 sequences of all HBV genotypes available in public databases and 958,000 sequences generated by means of ultradeep pyrosequencing of sequences from a homogenous population of 73 treatment-naive patients infected with HBV genotype D. Our data revealed that (i) the putative 4th catalytic residue displays unexpected variability that could be explained by the overlap of the HBx gene and has no apparent impact on HBV replicative capacity and that (ii) the C-helix-containing basic protrusion, which is required to guide the RNA/DNA heteroduplex into the catalytic site, is highly conserved and bears unique structural properties that can be used to target HBV-specific RNase H inhibitors without cross-species activity. The model shows substantial differences from other known RNases H and paves the way for functional and structural studies as a prerequisite to the development of new inhibitors of the HBV cell cycle specifically targeting RNase H activity.

DOI10.1128/JVI.03000-13
Alternate JournalJ. Virol.
PubMed ID24173223
PubMed Central IDPMC3911741

Επικοινωνία

Γραμματεία Τμήματος Ιατρικής T.K. 54124 Θεσσαλονίκη
 

Συνδεθείτε

Το τμήμα Ιατρικής στα social networks.
Ακολουθήστε μας ή συνδεθείτε μαζί μας.