Itacitinib for COVID-19

AbstractHuman organoids recapitulate the cell type diversity and function of their primary organs holding tremendous potentials for basic and translational research. Advances in single‐cell RNA sequencing (scRNA‐seq) technology and genome‐wide association study (GWAS) have accelerated the biological and therapeutic interpretation of trait‐relevant cell types or states. Here, we constructed a computational framework to integrate atlas‐level organoid scRNA‐seq data, GWAS summary statistics, expression quantitative trait loci, and gene–drug interaction data for distinguishing critical cell populations and drug targets relevant to coronavirus disease 2019 (COVID‐19) severity. We found that 39 cell types across eight kinds of organoids were significantly associated with COVID‐19 outcomes. Notably, subset of lung mesenchymal stem cells increased proximity with fibroblasts predisposed to repair COVID‐19‐damaged lung tissue. Brain endothelial cell subset exhibited significant associations with severe COVID‐19, and this cell subset showed a notable increase in cell‐to‐cell interactions with other brain cell types, including microglia. We repurposed 33 druggable genes, including IFNAR2, TYK2, and VIPR2, and their interacting drugs for COVID‐19 in a cell‐type‐specific manner. Overall, our results showcase that host genetic determinants have cellular‐specific contribution to COVID‐19 severity, and identification of cell type‐specific drug targets may facilitate to develop effective therapeutics for treating severe COVID‐19 and its complications.

Abstract Motivation Since December 2019, the newly identified coronavirus SARS-CoV-2 has caused a massive health crisis worldwide and resulted in over 70 000 COVID-19 infections so far. Clinical drugs targeting SARS-CoV-2 are urgently needed to decrease the high fatality rate of confirmed COVID-19 patients. Traditional de novo drug discovery needs more than 10 years, so drug repurposing seems the best option currently to find potential drugs for treating COVID-19. Results Compared with traditional non-covalent drugs, covalent drugs have attracted escalating attention recent years due to their advantages in potential specificity upon careful design, efficiency and patient burden. We recently developed a computational protocol named as SCAR (steric-clashes alleviating receptors) for discovering covalent drugs. In this work, we used the SCAR protocol to identify possible covalent drugs (approved or clinically tested) targeting the main protease (3CLpro) of SARS-CoV-2. We identified 11 potential hits, among which at least six hits were exclusively enriched by the SCAR protocol. Since the preclinical or clinical information of these identified drugs is already available, they might be ready for being clinically tested in the treatment of COVID-19. Contact senliu.ctgu@gmail.com

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2′-O-methyltransferase (2′-O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2′-O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2′-O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique “activating surface” between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed ≈9000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16/nsp10–drug complexes, we considered their pharmacological overlapping with functional modules of the virus–host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2′-O-methylation.