Biochemical investigation of novel DNJ-derivatives as alpha-glucosidase inhibitors in virus infected cells
The inhibition of a-glucosidase I and II in viral infected cells is reported to have a strong antiviral effect on enveloped viruses such as HCV. Due to this inhibition, glycoproteins cannot be correctly folded within the ER and therefore targeted by ERAD for degradation. The two viral proteins E1 and E2, which are very important for all steps of viral entry, cannot be build properly in the infected cells leading to non-infective viral particles. The new alpha-glucosidase inhibitor NAP-DNJ has a very strong inhibitory effect but is reported to be too cytotoxic for clinical use.
Fig. 1: Structure of NAP-DNJ
In this project, novel alpha-glucosidase inhibitors have been designed based on rational redesign of known inhibitors such as NAP-DNJ revealing the role of different parts of the molecule e.g. the bridging atom between alkyl chain and an arene residue as well as the functional groups, electronic properties or hydrophobicity of the arene itself. The novel alpha-glucosidase inhibitors are not only less cytotoxic, they are also capable of inhibiting both alpha-glucosidases I and II in a dose-dependent manner. One of the new compounds triggers non-proteasomal degradation in tissue culture.