Poxviruses Bearing DNA Polymerase Mutations Show Complex Patterns of Cross-Resistance.
Poxviruses Bearing DNA Polymerase Mutations Show Complex Patterns of Cross-Resistance.
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DOI：
10.3390/biomedicines10030580
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发表时间：
2022-03-01
期刊：
影响因子：
4.7
通讯作者：
Snoeck R
中科院分区：
文献类型：
--
作者：
Andrei G;Fiten P;Krečmerová M;Opdenakker G;Topalis D;Snoeck R
尽管天花在四十年前就被消灭了，但痘病毒仍然对人类和动物构成威胁。抗痘病毒药物的库非常有限，了解针对病毒 DNA 聚合酶的药物的耐药机制是抗病毒疗法开发的基础。我们在这里描述了在选择压力下用不同的无环核苷磷酸盐分离的痘病毒DNA聚合酶突变体的表型和基因型特征，包括HMPPC（西多福韦）、cHPMPC、HPMPA、cHPMPA、HPMPDAP、HMPPO-DAPy和PMEO-DAPy，以及焦磷酸类似物膦酰乙酸。对药物压力下出现的痘苗病毒 (VACV) 和牛痘病毒耐药病毒克隆进行了表型（药物敏感性谱）和基因型（DNA 聚合酶测序）特征。聚合酶结构域和 3'-5' 核酸外切酶结构域中的不同氨基酸变化与耐药性相关。当病毒获得突变组合时，3'-5'结构域的变化比聚合酶结构域更早出现。我们的研究强调了痘病毒 DNA 聚合酶残基 314、613、684、688 和 851 的重要性，这些残基先前与耐药性相关，并在 3'-5' 核酸外切酶结构域（M313I、F354L、D480Y）和 DNA 聚合酶结构域（A632T、T831I、E856K、L924F）中发现了一些新的突变。具有不同的药物敏感性特征。此外，突变的组合导致了复杂的交叉耐药模式。对带有新描述的突变的 VACV DNA 聚合酶进行建模，以了解这些突变对病毒酶结构的影响。我们证明了耐药 DNA 聚合酶突变以复杂的模式出现，需要考虑，以防此类突变最终出现在临床上。
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.
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影响因子：
7.6
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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