INSERM, CHU Limoges, University of Limoges, RESINFIT, U1092, F-87000 Limoges, France.
CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, National Reference Center for Herpesviruses (NRCHV), F-87000 Limoges, France.
Viruses. 2021 Aug 18;13(8):1638. doi: 10.3390/v13081638.
Human cytomegalovirus (HCMV) can cause serious diseases in immunocompromised patients. Current antiviral inhibitors all target the viral DNA polymerase. They have adverse effects, and prolonged treatment can select for drug resistance mutations. Thus, new drugs targeting other stages of replication are an urgent need. The terminase complex (pUL56-pUL89-pUL51) is highly specific, has no counterpart in the human organism, and thus represents a target of choice for new antivirals development. This complex is required for DNA processing and packaging. pUL52 was shown to be essential for the cleavage of concatemeric HCMV DNA and crucial for viral replication, but its functional domains are not yet identified. Polymorphism analysis was performed by sequencing from 61 HCMV naive strains and from 14 HCMV strains from patients treated with letermovir. Using sequence alignment and homology modeling, we identified conserved regions and potential functional motifs within the pUL52 sequence. Recombinant viruses were generated with specific serine or alanine substitutions in these putative patterns. Within conserved regions, we identified residues essential for viral replication probably involved in CXXC-like or zinc finger motifs. These results suggest that they are essential for pUL52 structure/function. Thus, these patterns represent potential targets for the development of new antivirals.
人巨细胞病毒（HCMV）可导致免疫功能低下患者发生严重疾病。目前的抗病毒抑制剂均靶向病毒 DNA 聚合酶。它们具有不良反应，长期治疗会选择出耐药突变。因此，迫切需要针对复制其他阶段的新药。末端酶复合物（pUL56-pUL89-pUL51）高度特异，在人体中没有对应物，因此是开发新抗病毒药物的首选靶标。该复合物是 DNA 加工和包装所必需的。已经表明 pUL52 对于切割连接的 HCMV DNA 是必需的，并且对病毒复制至关重要，但它的功能域尚未确定。通过对 61 株 HCMV 原始株和 14 株经来特莫韦治疗的患者的 HCMV 株进行测序，进行了多态性分析。通过序列比对和同源建模，我们在 pUL52 序列中鉴定了保守区域和潜在的功能基序。在这些假定的模式中，用特异性丝氨酸或丙氨酸取代生成了重组病毒。在保守区域内，我们鉴定了可能涉及CXXC 样或锌指基序的对病毒复制至关重要的残基。这些结果表明它们对 pUL52 的结构/功能是必需的。因此，这些模式代表了开发新抗病毒药物的潜在靶标。
