Heteroaryldihydropyrimidine (HAP) and Sulfamoylbenzamide (SBA) Inhibit Hepatitis B Virus Replication by Different Molecular Mechanisms.
Heteroaryldihydropyrimidine (HAP) and Sulfamoylbenzamide (SBA) Inhibit Hepatitis B Virus Replication by Different Molecular Mechanisms.
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DOI：
10.1038/srep42374
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发表时间：
2017-02-13
影响因子：
4.6
通讯作者：
Qin N
中科院分区：
文献类型：
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作者：
Zhou Z;Hu T;Zhou X;Wildum S;Garcia-Alcalde F;Xu Z;Wu D;Mao Y;Tian X;Zhou Y;Shen F;Zhang Z;Tang G;Najera I;Yang G;Shen HC;Young JA;Qin N
杂芳基二氢嘧啶 (HAP) 和氨磺酰苯甲酰胺 (SBA) 是有前途的非核苷 HBV 复制抑制剂。众所周知，HAP 会促进核心蛋白错误组装，但异常组装的分子机制仍不清楚。同样，SBA 诱导的核心蛋白的组装状态仍然未知。在这里，我们表明，与 HAP 不同，SBA 不会促进核心蛋白错误组装。有趣的是，两种参考化合物 HAP_R01 和 SBA_R01 与核心蛋白 Y132A 六聚体晶体结构中二聚体-二聚体界面的同一个口袋结合。显着的差异在于独特的疏水亚袋，该亚袋被 HAP_R01 的噻唑基团占据，但不受 SBA_R01 的干扰。光亲和标记证实了 HAP_R01 在衣壳二聚体-二聚体界面处的结合姿势，并提出了 HAP 诱导错误组装的新机制。根据晶体结构的共同特征，我们预测 T33 突变会对两种化合物产生类似的敏感性变化。相反，与HAP特异性群体（P25A、P25S或V124F）密切接触的位置处的突变仅降低对HAP_R01的易感性，但不降低对SBA_R01的易感性。因此，HAP 和 SBA 可能具有独特的耐药性特征。值得注意的是，P25S 和 V124F 替代存在于初治患者的低丰度准种中，这表明潜在的临床相关性。
Heteroaryldihydropyrimidine (HAP) and sulfamoylbenzamide (SBA) are promising non-nucleos(t)ide HBV replication inhibitors. HAPs are known to promote core protein mis-assembly, but the molecular mechanism of abnormal assembly is still elusive. Likewise, the assembly status of core protein induced by SBA remains unknown. Here we show that SBA, unlike HAP, does not promote core protein mis-assembly. Interestingly, two reference compounds HAP_R01 and SBA_R01 bind to the same pocket at the dimer-dimer interface in the crystal structures of core protein Y132A hexamer. The striking difference lies in a unique hydrophobic subpocket that is occupied by the thiazole group of HAP_R01, but is unperturbed by SBA_R01. Photoaffinity labeling confirms the HAP_R01 binding pose at the dimer-dimer interface on capsid and suggests a new mechanism of HAP-induced mis-assembly. Based on the common features in crystal structures we predict that T33 mutations generate similar susceptibility changes to both compounds. In contrast, mutations at positions in close contact with HAP-specific groups (P25A, P25S, or V124F) only reduce susceptibility to HAP_R01, but not to SBA_R01. Thus, HAP and SBA are likely to have distinctive resistance profiles. Notably, P25S and V124F substitutions exist in low-abundance quasispecies in treatment-naïve patients, suggesting potential clinical relevance.