Funded Project (2022-2024)CoVLP Production of SARS-CoV-2 virus like particles for drug screening and diagnostic validation

The SARS-CoV-2 pandemic has underscored the need for both new anti-viral drugs and highly sensitive diagnostic assays. For both drug screening and diagnostic validation, one usually uses patient-derived material from the clinics. As an attractive alternative, one can produce SARS-CoV-2 virus-like particles (VLPs) by transfecting appropriate cell lines with the structural proteins of SARS-CoV-2. Due to the absence of the viral genome, these particles are not infectious and can be handled at BSL-1 conditions but provide a versatile and safe tool for vaccine production, drug screening, virus neutralization assays and validation of antigen test sensitivity. In addition, any structural component, particularly the S spike protein, can be exchanged and modified to study its structural role and to develop new functionalities. While SARS-CoV-2 VLP production has already been established, a lack of any structural analysis of the VLP limits their applicability in translational research and diagnostics. We will use cryo-electron tomography and continuum modelling to characterize the structure and assembly of VLP carrying different spike proteins. To improve our quantitative understanding of VLP production, the aim is to develop mathematical models for membrane curvature generation by structural proteins. We plan to establish VLP assays together with bioinformatics and computational physical simulation approaches to predict and test the interaction of heparan sulfates and the structurally similar heparin with an S spike of different variants for aiding the rational design of heparin analogues as multitarget therapeutic agents. Overall, this study will provide further insight into the structure and assembly of SARS-CoV-2 and will provide a valuable VLP toolkit which will be used as a validation standard for diagnostics, viral entry and drug screening assays.