Protecting the brain from COVID-19-mediated neurodegeneration through inflammasome inhibition

The COVID-19 infection is associated with detrimental manifestations at the brain and neurological levels that are linked to excess SARS-CoV-2-induced inflammation. Indeed, recent results demonstrated an increased risk of neurological and psychiatric disorders in the six months after a COVID-19 diagnosis, in particular in patients who require hospitalization or admission to the intensive therapy units (Taquet et al. Lancet Psychiatry 2021. doi: 10.1016/S2215-0366(21)00084- 5). Moreover, injurious effects on the nervous system in the long term have been also anticipated (Iadecola et al. Cell 2020, 183 16. doi: 10.1016/j.cell.2020.08.028). Patients suffering from neurological conditions are even more susceptible to develop a SARS-CoV-2 infection and to related neurological damage. The main mechanism involved is neuroinflammation, a critical process in psychiatric and neurodegenerative disease development. The overarching goal of our project (BRAVE) is to develop, optimize and expand new drug candidates against SARS-CoV-2-induced inflammatory responses by targeting NLRP3, the main protein effector involved in the mechanisms leading to brain disorders and neurodegeneration. It is now established that SARS-CoV-2 infection induces a cytokine storm that can trigger and exacerbate neuroinflammatory processes. The stress induced by the cytokine storm, the neuroimmune response and the neuroinvasion of the virus through the blood brain barrier (BBB), leads to increased extracellular levels of ATP that can hyperactivate the P2X7 receptors, ATP-gated ion channels widely expressed through the body and in the central nervous system (CNS) cells. Once activated, P2X7, in turn, stimulates the activation and assembly of the NLRP3 inflammasome. This cascade is hypothesized to lead to a further increase in neuroinflammation and COVID-19- associated psychiatric disorders and neurodegenerative diseases. NLRP3 acts as a hub protein that activates and links different inflammation pathways, which may occur in COVID-19, Alzheimer pathology (Ising et al. Nature 2019, 575, 669. doi: 10.1038/s41586- 019-1769-z), and acute respiratory distress syndrome (ARDS), whose survivors also exhibit increased incidence of long-term depression, anxiety and cognitive impairment (Hopkins et al. Am J Respir Crit Care Med 2005, 171, 340. doi: 10.1164/rccm.200406-763OC). These observations suggest that inhibiting the inflammasome activation, by targeting NLRP3-centered mechanisms and proteinprotein interactions (PPIs), can be a promising strategy to prevent or treat neurological complications, and many other COVID-induced effects in infected patients. Intervention on these mechanisms can in principle impact on diverse COVID-related neurological manifestations, either dependent on non-resolving inflammation or on dysregulated immunity. Drugs developed in this context would help keep most people, and in particular those at risk, out of hospital and avoid progression into severe COVID and post-COVID neurological manifestations. In this framework, given the lack of structural information and knowledge on the mechanism of action of NLRP3 inhibitors, we aim to deliver structural, dynamics, and network interaction models to elucidate the determinants of their activity and lay the grounds for further optimization. Our project is based on solid preliminary experimental and computational data on newly designed NLRP3 inhibitors and on novel methods to characterize the dynamic cross-talk between ligands, proteins, and their networks of interactions. The latter approaches will be complemented by molecular and subcellular tools developed by T5.1 and T5.17 in WP5 and currently being implemented in the EBRAINS platform. Therefore, the proposed research will also contribute to further broaden the portfolio of molecular/subcellular modeling approaches offered on EBRAINS, as well as the applicability of such tools to molecular targets relevant for bra