Session Title: Parallel Session: HEPATITIS B
Presentation Date: 01 APR, 2011
NOVEL PEPTIDE-BASED MICROBIOCIDES INHIBITING HEPATITIS B VIRUS ENTRY BY PREVENTING VIRUS INTERACTION WITH THE CELL SURFACE
J. Lucifora1*, I. Kowalski2, Y. Xia1, K. Brandenburg2, U. Protzer1
1Institute of Virology, Technische Universität München / Helmholtz Zentrum München, Munich, 2Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Naturwissenschaften, Borstel, Germany. ****@****
Background and aims: Current treatment regimens usually fail to cure chronically HBV-infected patients. Most approved therapies are targeting the viral polymerase activity without preventing virus entry and formation of the very stable HBV transcription template, leading to viral rebound after treatment arrest or to development of viral resistance in case of prolonged treatment. Development of entry inhibitors is thus very important and will improve therapeutic options but also prevent vertical transmission and reinfection after liver transplantation or serve as post-exposure prophylaxis.
Methods: Synthetic anti-lipopolysaccharide peptides (SALP) were designed, synthesized and tested for their antiviral effect using HBV-infected HepaRG cells.
Results: We showed that polycationic amphiphilic SALP very efficiently and dose dependently inhibit HBV infection if cells are treated prior and during infection. All the HBV markers (including cccDNA, HBV-RNA, HBeAg, HBsAg, intracellular rc-DNA) were reduced from 50% between the concentration ranges of 0.5 to 2 µg/mL and from 90% between 4 to 5 µg/mL without any toxicity observed. No effect was seen in cells treated after HBV infection. Using different peptides, we showed that overall positive charges and their equal distribution over the peptide, rather than the sequence or the hydrophobicity of the peptides, seem to determine entry inhibition. By heparin affinity chromatography of HBV particles in presence of SALP we observed that HBV particles binding to heparin was 60 % reduced, suggesting that SALP compete with HBV for binding to heparin.
Conclusions: Altogether, our results demonstrated that SALP inhibit initial binding of HBV to the cell surface by direct interaction to heparan sulfate. In parallel, SALP were demonstrated to be also active against e.g. HIV or herpes viruses and to exhibit broad antimicrobial potential in mice models of peritonitis, colitis, and pneumonia. Thus, SALP represent a very promising therapeutic strategy to treat virus infection with concomitant bacterial infection that often lead to life-threatening systemic complications such peritonitis accompanying HBV- or HCV-related liver cirrhosis.