De Novo Macrocyclic Peptide Inhibitors of Hepatitis B Virus Cellular Entry

Toby Passioura; Koichi Watashi; Kento Fukano; Satomi Shimura; Wakana Saso; Ryo Morishita; Yuki Ogasawara; Yasuhito Tanaka; Masashi Mizokami; Camille Sureau; Hiroaki Suga; Takaji Wakita

doi:10.1016/j.chembiol.2018.04.011

De Novo Macrocyclic Peptide Inhibitors of Hepatitis B Virus Cellular Entry

Cell Chem Biol. 2018 Jul 19;25(7):906-915.e5. doi: 10.1016/j.chembiol.2018.04.011. Epub 2018 May 17.

Authors

Affiliations

¹ Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
² Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Applied Biological Sciences, Tokyo University of Science, Noda 278-8510, Japan; JST CREST, Saitama 332-0012, Japan.
³ Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Analytical Biochemistry, Meiji Pharmaceutical University, Kiyose 204-8588, Japan.
⁴ Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
⁵ Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
⁶ CellFree Sciences Co., Ltd., Matsuyama 790-8577, Japan.
⁷ Department of Analytical Biochemistry, Meiji Pharmaceutical University, Kiyose 204-8588, Japan.
⁸ Department of Virology and Liver Unit, Nagoya City University, Graduate School of Medicinal Sciences, Nagoya 467-8601, Japan.
⁹ Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan.
¹⁰ Laboratoire de Virologie Moléculaire, Institut National de la Transfusion Sanguine, INSERM U1134, Paris 75015, France.
¹¹ Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan; JST CREST, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: hsuga@chem.s.u-tokyo.ac.jp.
¹² Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan. Electronic address: wakita@nih.go.jp.

PMID: 29779957
DOI: 10.1016/j.chembiol.2018.04.011

Abstract

Hepatitis B virus (HBV) constitutes a significant public health burden, and currently available treatment options are not generally curative, necessitating the development of new therapeutics. Here we have applied random non-standard peptide integrated discovery (RaPID) screening to identify small macrocyclic peptide inhibitors of HBV entry that target the cell-surface receptor for HBV, sodium taurocholate cotransporting polypeptide (NTCP). In addition to their anti-HBV activity, these molecules also inhibit cellular entry by the related hepatitis D virus (HDV), and are active against diverse strains of HBV (including clinically relevant nucleos(t)ide analog-resistant and vaccine escaping strains). Importantly, these macrocyclic peptides, in contrast to other NTCP-binding HBV entry inhibitors, exhibited no inhibition of NTCP-mediated bile acid uptake, making them appealing candidates for therapeutic development.

Keywords: HBV; HDV; NTCP; RaPID; bile acid; cyclosporin; entry; inhibitor; macrocyclic; transporter.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Hep G2 Cells
Hepatitis B virus / drug effects*
Hepatitis B virus / metabolism
Humans
Macrocyclic Compounds / chemistry
Macrocyclic Compounds / pharmacology*
Microbial Sensitivity Tests
Molecular Conformation
Peptides / chemistry
Peptides / pharmacology*
Receptors, Cell Surface / antagonists & inhibitors*
Receptors, Cell Surface / metabolism
Taurocholic Acid / chemistry
Taurocholic Acid / pharmacology

Substances

Antiviral Agents
Macrocyclic Compounds
Peptides
Receptors, Cell Surface
Taurocholic Acid