PIK-93 for COVID-19

Abstract Background Neurological complications are a significant concern of Coronavirus Disease 2019 (COVID-19). However, the pathogenic mechanism of neurological symptoms associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is poorly understood. Methods We used Drosophila as a model to systematically analyze SARS-CoV-2 genes encoding structural and accessory proteins and identified the membrane protein (M) that disrupted mitochondrial functions in vivo. The M protein was stereotaxically injected to further assess its effects in the brains of wild-type (WT) and 5 × FAD mice. Omics technologies, including RNA sequencing and interactome analysis, were performed to explore the mechanisms of the effects of M protein both in vitro and in vivo. Results Systematic analysis of SARS-CoV-2 structural and accessory proteins in Drosophila identified that the M protein induces mitochondrial fragmentation and dysfunction, leading to reduced ATP production, ROS overproduction, and eventually cell death in the indirect flight muscles. In WT mice, M caused hippocampal atrophy, neural apoptosis, glial activation, and mitochondrial damage. These changes were further aggravated in 5 × FAD mice. M was localized to the Golgi apparatus and genetically interacted with four wheel drive (FWD, a Drosophila homolog of mammalian PI4KIIIβ) to regulate Golgi functions in flies. Fwd RNAi, but not PI4KIIIα RNAi, reversed the M-induced Golgi abnormality, mitochondrial fragmentation, and ATP reduction. Inhibition of PI4KIIIβ activity suppressed the M-induced neuronal cell death. Therefore, M induced mitochondrial fragmentation and apoptosis likely through disruption of Golgi-derived PI(4)P-containing vesicles. Conclusions M disturbs the distribution and function of Golgi, leading to mitochondrial abnormality and eventually neurodegeneration via a PI4KIIIβ-mediated mechanism. This study reveals a potential mechanism for COVID-19 neurological symptoms and opens a new avenue for development of therapeutic strategies targeting SARS-CoV-2 M or mitochondria.

Inositol plays many important roles in cellular processes through its various derivatives including phosphatidylinositol phosphates. Viruses use phosphatidylinositol phosphates for their replication in multiple processes including entry, formation of replication organelles, assembly and release. For these processes, viruses recruit phosphatidylinositol kinases to meet their demand of phosphatidylinositol phosphates. Inhibitors of phosphatidylinositol kinases have been shown to inhibit various viruses. The complexity of various types and isoforms of phosphatidylinositol kinases can be a problem in developing a broad-spectrum antiviral as different viruses use various types and isoforms of the enzyme. Inositol monophosphatase is an enzyme required for both de novo biosynthesis and intracellular recycling of inositol. It can provide a chokepoint to limit the availability of cellular inositol, phosphatidylinositol, and phosphatidylinositol phosphates. It can be a promising target for broad-spectrum antiviral development.