Degradation of ZIKV and DENV Envelope Protein Through Selective Targeting to ERAD Pathway

Purpose: In the last decades, flaviviruses have contributed majorly in the global mortality and disabilities, posing a dire need for desigining novel strategies to combat these infection. Methods & Materials: The endoplasmic reticulum associated degradation pathway (ERAD) is the quality control mechanism of the cell for proteins within the secretory pathway which detects terminally unfolded or misfolded proteins and recruit them to proteasomal degradation through recognition by SEL1L protein. We have developed a strategy to exploit the ERAD pathway for induction of specific degradation of the viral envelope E protein using novel recombinant fusion proteins called degradins. These molecules are formed by an N terminal moiety with target specific binding activity and a SEL1L moiety, which effectively targets the protein to ERAD. Results: The screening of a VHH based phage-display library identified DENV2 and ZIKV specific antibodies which recognize E protein within the ER, both as secretory and membrane bound forms targeting them to proteasomal degradation following retro-translocation to the cytosol. These molecules were observed to significantly reduce the production of DENV2, ZIKV and WNV pseudoviral particles. Conclusion: This technique represents an effective mechanism to knock-out viral proteins within the secretory pathway with high specificity and selectivity.