High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein.

Klaus Klumpp, Angela M Lam, Christine Lukacs, Robert Vogel, Suping Ren, Christine Espiritu, Ruth Baydo, Kateri Atkins, Jan Abendroth, Guochun Liao, Andrey Efimov, George Hartman, Osvaldo A Flores

Proceedings of the National Academy of Sciences of the United States of America 2015 Dec 8

filter terms:

The hepatitis B virus (HBV) core protein is essential for HBV replication and an important target for antiviral drug discovery. We report the first, to our knowledge, high-resolution crystal structure of an antiviral compound bound to the HBV core protein. The compound NVR-010-001-E2 can induce assembly of the HBV core wild-type and Y132A mutant proteins and thermostabilize the proteins with a Tm increase of more than 10 °C. NVR-010-001-E2 binds at the dimer-dimer interface of the core proteins, forms a new interaction surface promoting protein-protein interaction, induces protein assembly, and increases stability. The impact of naturally occurring core protein mutations on antiviral activity correlates with NVR-010-001-E2 binding interactions determined by crystallography. The crystal structure provides understanding of a drug efficacy mechanism related to the induction and stabilization of protein-protein interactions and enables structure-guided design to improve antiviral potency and drug-like properties.

Citation

Klaus Klumpp, Angela M Lam, Christine Lukacs, Robert Vogel, Suping Ren, Christine Espiritu, Ruth Baydo, Kateri Atkins, Jan Abendroth, Guochun Liao, Andrey Efimov, George Hartman, Osvaldo A Flores. High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein. Proceedings of the National Academy of Sciences of the United States of America. 2015 Dec 8;112(49):15196-201