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Inhibition of Hepatitis B Virus Replication by Drug-Induced Depletion of Nucleocapsids
Karl Deres,1*Claus H. Schröder,7*Arnold Paessens,1Siegfried Goldmann,2Hans Jörg Hacker,7Olaf Weber,8Thomas Krämer,2Ulrich Niewöhner,2Ulrich Pleiss,3Jürgen Stoltefuss,2Erwin Graef,1Diana Koletzki,1Ralf N. A. Masantschek,1Anja Reimann,7Rainer Jaeger,5Rainer Groß,6Bernhard Beckermann,4Karl-Heinz Schlemmer,4Dieter Haebich,2Helga Rübsamen-Waigmann1
Chronic hepatitis B virus (HBV) infection is a major
cause of liver disease. Only interferon- and the nucleosidic
inhibitorsof the viral polymerase, 3TC and adefovir, are approved for
therapy.However, these therapies are limited by the side effects of
interferonand the substantial resistance of the virus to nucleosidic
inhibitors.Potent new antiviral compounds suitable for monotherapy or
combinationtherapy are highly desired. We describe non-nucleosidic
inhibitorsof HBV nucleocapsid maturation that possess in vitro and in
vivoantiviral activity. These inhibitors have potential for futuretherapeutic regimens to combat chronic HBV infection.
Department of 1 Virology, 2 Chemistry,
3 Isotope Chemistry, 4 Preclinical
Pharmakokinetics, 5 Toxicology, 6 Safety
Pharmacology, Bayer Research Center, Wuppertal, Germany.
7 Deutsches Krebsforschungszentrum, Virus-Host-Interactions,
Heidelberg, Germany. 8 Bayer Corporation, Pharmaceutical
Division, 400 Morgan Lane, West Haven, CT 06516-4175, USA.
*
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail:
karl.deres.kd1{at}bayer-ag.de (K.D.); c.schroeder{at}dkfz.de
(C.H.S.); arnold.paessens.ap{at}bayer-ag.de(A.P.);
helga.ruebsamen-waigmann.hr{at}bayer-ag.de (H.R.-W.)
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and the nucleosidic
inhibitors of the viral polymerase, 3TC and adefovir, are approved for
therapy. However, these therapies are limited by the side effects of
interferon and the substantial resistance of the virus to nucleosidic
inhibitors. Potent new antiviral compounds suitable for monotherapy or
combination therapy are highly desired. We describe non-nucleosidic
inhibitors of HBV nucleocapsid maturation that possess in vitro and in
vivo antiviral activity. These inhibitors have potential for future therapeutic regimens to combat chronic HBV infection.
