title: High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein.
abstract: 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.
authors.affiliation: Novira Therapeutics, Doylestown, PA 18902; kklumpp@noviratherapeutics.com.
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
authors.affiliation: Novira Therapeutics, Doylestown, PA 18902;
authors.forename: Angela M
authors.initials: AM
authors.lastname: Lam
authors.affiliation: Beryllium, Bedford, MA 01730;
authors.forename: Christine
authors.initials: C
authors.lastname: Lukacs
authors.affiliation: Novira Therapeutics, Doylestown, PA 18902;
authors.forename: Robert
authors.initials: R
authors.lastname: Vogel
authors.affiliation: Novira Therapeutics, Doylestown, PA 18902;
authors.forename: Suping
authors.initials: S
authors.lastname: Ren
authors.affiliation: Novira Therapeutics, Doylestown, PA 18902;
authors.forename: Christine
authors.initials: C
authors.lastname: Espiritu
authors.affiliation: Beryllium, Bedford, MA 01730;
authors.forename: Ruth
authors.initials: R
authors.lastname: Baydo
authors.affiliation: Beryllium, Bedford, MA 01730;
authors.forename: Kateri
authors.initials: K
authors.lastname: Atkins
authors.affiliation: Beryllium, Bedford, MA 01730;
authors.forename: Jan
authors.initials: J
authors.lastname: Abendroth
authors.affiliation: Vista Informatics Corporation, San Mateo, CA 94403;
authors.forename: Guochun
authors.initials: G
authors.lastname: Liao
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Andrey
authors.initials: A
authors.lastname: Efimov
authors.affiliation: Novira Therapeutics, Doylestown, PA 18902;
authors.forename: George
authors.initials: G
authors.lastname: Hartman
authors.affiliation: Novira Therapeutics, Doylestown, PA 18902;
authors.forename: Osvaldo A
authors.initials: OA
authors.lastname: Flores
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006515:Hepatitis B virus / Q000502:physiology*; D011487:Protein Conformation; D014758:Viral Core Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D014758:Viral Core Proteins
keywords: HBV inhibitor; HBV treatment; capsid; core; protein–protein interaction