Inactivation of the Niemann Pick C1 protein as a strategy to inhibit SARS-CoV2 infection

There is a great effort from scientists around the globe to identify efficacious drugs capable for preventing or treating COVID-19 pandemic. Although different tissues and organs can be affected by SARS-CoV2 infection, the lung establishes the primary path for virus entrance to the human body and potentially explains the high efficiency of transmission and diffusion. Then, the lower respiratory tract infection leads to a life-threatening condition. The SARS-CoV2 life cycle relies on a number of host cell factors that are common among enveloped viruses and are largely characterized. This knowledge provides a solid ground for conceiving and establishing reliable model systems to study the biological underpinning of COVID-19 pathophysiology and to assess the efficacy of drugs. A significant convergence exists between the mechanistic processes of SARS-Cov2 cell-cycle and the cellular alterations associated to the lack of function of the NPC1 protein. These alterations affect the integrity of lipid-enriched plasma membrane microdomains and the endocytic pathway, which are involved in virus recognition and mobilization inside the cell, respectively. Thus, the NPC1 phenotype provides an intrinsic “unfavorable” host environment for virus entry and propagation that has been already demonstrated for Ebola, SARS, MERS and HIV. We will generate and validate two cellular models that are based on lung-derived cell types and have been conceived to investigate the relationship between the NPC1 protein function and SARS-CoV2 infectivity. To further support this relationship we will also exploit clinically approved NPC1-inactivating drugs that appear to be provided with high drug-repositioning potential.