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.

• Klíčová slova
• DNA polymerase, cidofovir, drug resistance, nucleotide analogues, phosphonoacetic acid, vaccinia virus,
• Publikační typ
• časopisecké články MeSH

The 32nd International Conference on Antiviral Research (ICAR), sponsored by the International Society for Antiviral Research (ISAR), was held in Baltimore, Maryland, USA, on May 12-15, 2019. This report gives an overview of the conference on behalf of the Society. It provides a general review of the meeting and awardees, summarizing the presentations, and their main conclusions from the perspective of researchers active in many different areas of antiviral research and development. As in past years, ICAR promoted and showcased the most recent progress in antiviral research, and continued to foster collaborations and interactions in drug discovery and development. The 33rd ICAR will be held in Seattle, Washington, USA, March 30th-April 3rd, 2020.

• MeSH
• antivirové látky * chemie   farmakologie   terapeutické užití   MeSH
• farmaceutická chemie MeSH
• farmaceutická technologie MeSH
• internacionalita MeSH
• lidé MeSH
• objevování léků MeSH
• virové nemoci farmakoterapie   patofyziologie   virologie   MeSH
• výzkum * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antivirové látky * MeSH