Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):15196-201. doi: 10.1073/pnas.1513803112. Epub 2015 Nov 23.

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

Author information

1
Novira Therapeutics, Doylestown, PA 18902; kklumpp@noviratherapeutics.com.
2
Novira Therapeutics, Doylestown, PA 18902;
3
Beryllium, Bedford, MA 01730;
4
Vista Informatics Corporation, San Mateo, CA 94403;
5
Fox Chase Cancer Center, Philadelphia, PA 19111.

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.

KEYWORDS:

HBV inhibitor; HBV treatment; capsid; core; protein–protein interaction

PMID:
26598693
PMCID:
PMC4679053
DOI:
10.1073/pnas.1513803112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center