Dengue virus (DENV) challenges vaccine design due to antibody-dependent enhancement (ADE) and evidence suggests that Zika virus (ZIKV) experiences ADE with DENV and West Nile virus (WNV) antibodies. Thus, multiple flaviviruses must be considered when developing novel therapies against ZIKV. We analyzed 42 flavivirus polyproteins in their evolutionary context to identify motifs conserved in sequence with low real-time and evolutionary conformational flexibility, thought to be fitness-critical sites. We also analyzed evolutionary rate-shifts between clades for insight on vector specificity. For mosquito-borne flaviviruses, two conserved motifs were identified within the RNA-dependent RNA polymerase (RdRP), critical for flavivirus genome replication. Clade-specific motifs were identified for the ZIKV+DENV and WNV clades, many of which were also in RdRP. Six sites in motifs for WNV experienced significant evolutionary rate-shifts, suggesting their importance for functional divergence. Overall, some of these motifs are prime candidates as broadly neutralizing antiviral drug targets across different mosquito-borne flaviviruses.

中文翻译：

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探索寨卡病毒、登革热病毒和其他黄病毒的蛋白质组中的进化约束，以找到适合健康的关键位点。

由于抗体依赖性增强 (ADE)，登革热病毒 (DENV) 对疫苗设计提出了挑战，并且有证据表明寨卡病毒 (ZIKV) 经历了 DENV 和西尼罗河病毒 (WNV) 抗体的 ADE。因此，在开发针对 ZIKV 的新疗法时，必须考虑多种黄病毒。我们分析了 42 种黄病毒多蛋白在其进化背景下的序列，以识别具有低实时性和进化构象灵活性的序列保守基序，这些基序被认为是健康关键位点。我们还分析了进化枝之间的进化速率变化，以了解载体特异性。对于蚊媒黄病毒，在依赖于 RNA 的 RNA 聚合酶 (RdRP) 中发现了两个保守的基序，这对黄病毒基因组复制至关重要。为 ZIKV+DENV 和 WNV 进化枝确定了进化枝特异性基序，其中许多也在 RdRP 中。WNV 图案中的六个位点经历了显着的进化速率变化，表明它们对功能差异的重要性。总体而言，这些基序中的一些是主要候选者，可作为广泛中和不同蚊媒黄病毒的抗病毒药物靶标。