Poxviruses Bearing DNA Polymerase Mutations Show Complex Patterns of Cross-Resistance
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F22%3A00556926" target="_blank" >RIV/61388963:_____/22:00556926 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.3390/biomedicines10030580" target="_blank" >https://doi.org/10.3390/biomedicines10030580</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3390/biomedicines10030580" target="_blank" >10.3390/biomedicines10030580</a>
Alternative languages
Result language
angličtina
Original language name
Poxviruses Bearing DNA Polymerase Mutations Show Complex Patterns of Cross-Resistance
Original language description
Despite the eradication of smallpox four decades ago, poxviruses continue to be a threat to humans and animals. The arsenal of anti-poxvirus agents is very limited and understanding mechanisms of resistance to agents targeting viral DNA polymerases is fundamental for the development of antiviral therapies. We describe here the phenotypic and genotypic characterization of poxvirus DNA polymerase mutants isolated under selective pressure with different acyclic nucleoside phosphonates, including HPMPC (cidofovir), cHPMPC, HPMPA, cHPMPA, HPMPDAP, HPMPO-DAPy, and PMEO-DAPy, and the pyrophosphate analogue phosphonoacetic acid. Vaccinia virus (VACV) and cowpox virus drug-resistant viral clones emerging under drug pressure were characterized phenotypically (drug-susceptibility profile) and genotypically (DNA polymerase sequencing). Different amino acid changes in the polymerase domain and in the 3'-5' exonuclease domain were linked to drug resistance. Changes in the 3'-5' domain emerged earlier than in the polymerase domain when viruses acquired a combination of mutations. Our study highlights the importance of poxvirus DNA polymerase residues 314, 613, 684, 688, and 851, previously linked to drug resistance, and identified several novel mutations in the 3'-5' exonuclease domain (M313I, F354L, D480Y) and in the DNA polymerase domain (A632T, T831I, E856K, L924F) associated with different drug-susceptibility profiles. Furthermore, a combination of mutations resulted in complex patterns of cross-resistance. Modeling of the VACV DNA polymerase bearing the newly described mutations was performed to understand the effects of these mutations on the structure of the viral enzyme. We demonstrated the emergence of drug-resistant DNA polymerase mutations in complex patterns to be considered in case such mutations should eventually arise in the clinic.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/LM2018133" target="_blank" >LM2018133: Czech National Node to the European Infrastructure for Translational Medicine</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Biomedicines
ISSN
2227-9059
e-ISSN
2227-9059
Volume of the periodical
10
Issue of the periodical within the volume
3
Country of publishing house
CH - SWITZERLAND
Number of pages
37
Pages from-to
580
UT code for WoS article
000776828000001
EID of the result in the Scopus database
2-s2.0-85126013950