Heteroaryldihydropyrimidine (HAP) and Sulfamoylbenzamide (SBA) Inhibit Hepatitis B Virus Replication by Different Molecular Mechanisms

• DOI: 10.1038/srep42374
• Publication Date: 2017-02-13T11:02:33Z
• Authors: Zheng Zhou; Taishan Hu; Xue Zhou; Steffen Wildum; Fernando Garcia-A...; Zhiheng Xu; Daitze Wu; Yi Mao; Xiaojun Tian; Yuan Zhou; Fang Shen; Zhisen Zhang; Guozhi Tang; Isabel Najera; Guang Yang; Hong C. Shen; John A. T. Young; Ning Qin
• Keywords: Random hexamer; Viral quasispecies

Abstract Heteroaryldihydropyrimidine (HAP) and sulfamoylbenzamide (SBA) are promising non-nucleos(t)ide HBV replication inhibitors. HAPs known to promote core protein mis-assembly, but the molecular mechanism of abnormal assembly is still elusive. Likewise, status induced by SBA remains unknown. Here we show that SBA, unlike HAP, does not mis-assembly. Interestingly, two reference compounds HAP_R01 SBA_R01 bind same pocket at dimer-dimer interface in crystal structures Y132A hexamer. The striking difference lies a unique hydrophobic subpocket occupied thiazole group , unperturbed . Photoaffinity labeling confirms binding pose on capsid suggests new HAP-induced Based common features predict T33 mutations generate similar susceptibility changes both compounds. In contrast, positions close contact with HAP-specific groups (P25A, P25S, or V124F) only reduce HAP_R01, Thus, HAP likely have distinctive resistance profiles. Notably, P25S V124F substitutions exist low-abundance quasispecies treatment-naïve patients, suggesting potential clinical relevance.