Thomas Jefferson University Background
Sigma1 is a novel ligand operated intracellular, integral membrane protein enriched in the secretory pathway, especially in the endoplasmic reticulum, of most cells. The multifunctionality of Sigma1 enables it to regulate lipid and protein homeostasis at multiple levels and it plays a critical role in protein synthesis, processing, trafficking, assembly, and quality control in the secretory pathway of cells. Thus, targeting Sigma1 enables selective modulation of multiple cellular processes via one drug target.
Using a pharmacophore-based approach, researchers at Thomas Jefferson University discovered that certain compounds with affinity for Sigma trigger protein and lipid regulatory mechanisms such as the unfolded protein response (UPR), autophagy, and associated lysosomal and protein trafficking mechanisms. In addition, for several difficult to treat viruses, including coronaviruses and flaviviruses, the Jefferson team has shown that genetic inhibition and certain pharmacological modulators of Sigma1 can be used to target, disrupt, and suppress viral life cycle, infection, and dissemination.
Researchers at Thomas Jefferson University have discovered and generated a series of drug-like Sigma inhibiting small molecule compounds with mechanisms of action consistent with anti-SARS-CoV drugs. It is proposed that these compounds and derivatives will be efficacious antiviral agents with an improved safety profile. The compounds, which have specifically been designed based on the Sigma mechanism of action, will be more efficacious and function via distinct mechanisms of action than existing clinical stage and preclinical investigational compounds. Experiments demonstrated that a novel drug-like Sigma1 inhibitor blocks infection and replication of multiple virus families, including Flavivirus (ZIKV, DENV, WNV, Powassan Virus), coronavirus (SARS-CoV2), and hepatitis virus (HCV). Importantly, the on-target actions of Sigma1 modulators do not induce adverse effects Sigma1 receptor knockout mice are viable and do not display a phenotype overtly different from wild type mice, indicating that Sigma1 inhibition has minimal impact on normal tissues.
Sigma1 inhibitors may induce degradation of a surface viral protein, which is key for viral infection, and this results in reduced or weakened viral infection and/or viral loads
Sigma1 inhibitors may be used to block several difficult to treat viruses, such as coronaviruses or flaviviruses.
Jefferson is currently seeking funding and partnerships for lead optimization and IND enabling studies.