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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