Zymoxins, HCV NS3 protease-activated chimeric toxins:a novel antiviral therapy for the treatment of HCV infections

The Technology

Rationally designed viral-protease activated chimeric toxins were developed (“Zymoxins”). The chimeric toxins were constructed by fusing diphtheria toxin A (DTA) or Ricin A chain (RTA), to an inhibitor peptide/domain (defensin for DTA; ribosome stalk peptide for RTS) via an HCV NS3 protease-cleavable linker, thus converting a constitutively active toxin to an HCV NS3 protease-activatable form.   The HCV NS3 protease is a virally encoded protease which expression and activity in infected cells is essential for viral replication/maturation. Thus these zymoxins are activated in HCV infected cells which specifically express HCV NS3 protease.   In addition, the Zymoxins were fused to the binding and translocation domain of Pseudomonas exotoxin A (PE) for efficient delivery to the cell cytosol, where the toxins inactivate elongation factor 2 (DTA) or inactivate ribosomes (RTA) and cause cell death. For increased specificity, the non-specific cell binding domain I of PE can be replaced with target-specific antibodies. 

Target population:

         Newly infected patients

         HCV patients undergoing liver transplantation 

Data-to-date

The Zymoxins demonstrated specific and efficient cytotoxicity to 293 cells that inducibly express the NS3 protease and to HCV infected hepatome cells and in the HCVcc model, in which recombinant infectious HCV particles are produced in cell culture based on the Huh7.5 hepatoma cell line. 

Patent

PCT/IL2011/000680

Project manager

Adi Elkeles
BD Manager

Project researchers

Itai Benhar
T.A.U Tel Aviv University, Life Sciences
Molecular Microbiology-Biotechnology

Ran TUR-KASPA
T.A.U Tel Aviv University, Medicine-Sackler Faculty
Felsenstein Medical Res Center-Beilinson