The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.

/pdf/drug-repurposing-screens-identify-chemical-entities-for-the-3rpkxtw5qw.pdf

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions.

The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the μ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin β3 and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions.

Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications.

The primary cell surface receptor for SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2). Recently it has been noticed that the viral Spike protein has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif resource, ELM, and were presented with candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton and cell signalling. These SLiM candidates are highly conserved in vertebrates. They suggest potential interactions with the AP2 mu2 subunit as well as I-BAR, LC3, PDZ, PTB and SH2 domains found in signalling and regulatory proteins present in epithelial lung cells. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, often involving tyrosine phosphorylation status. Candidate LIR motifs are present in the tails of ACE2 and integrin beta3, suggesting that these proteins can directly recruit autophagy components. We also noticed that the extracellular part of ACE2 has a conserved MIDAS structural motif, which are commonly used by beta integrins for ligand binding, potentially supporting the proposal that integrins and ACE2 share common ligands. The findings presented here identify several molecular links and testable hypotheses that might help uncover the mechanisms of SARS-CoV-2 attachment, entry and replication, and strengthen the possibility that it might be possible to develop host-directed therapies to dampen the efficiency of viral entry and hamper disease progression. The strong sequence conservation means that these putative SLiMs are good candidates: Nevertheless, SLiMs must always be validated by experimentation before they can be stated to be functional.

Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications

Our previous study showed that glycyrrhizin (GLY) inhibited porcine epidemic diarrhea virus (PEDV) infection, but the mechanisms of GLY anti-PEDV action remain unclear. In this study, we focused on the anti-PEDV and anti-proinflammatory cytokine secretion mechanisms of GLY. We found that PEDV infection had no effect on toll-like receptor 4 (TLR4) protein and mRNA levels, but that TLR4 regulated PEDV infection and the mRNA levels of proinflammatory cytokines. In addition, we demonstrated that TLR4 regulated p38 phosphorylation but not extracellular regulated protein kinases1/2 (Erk1/2) and c-Jun N-terminal kinases (JNK) phosphorylation, and that GLY inhibited p38 phosphorylation but not Erk1/2 and JNK phosphorylation. Therefore, we further explored the relationship between high mobility group box-1 (HMGB1) and p38. We demonstrated that inhibition of HMGB1 using an antibody, mutation, or knockdown decreased p38 phosphorylation. Thus, HMGB1 participated in activation of p38 through TLR4. Collectively, our data indicated that GLY inhibited PEDV infection and decreased proinflammatory cytokine secretion via the HMGB1/TLR4-mitogen-activated protein kinase (MAPK) p38 pathway.

Glycyrrhizin Inhibits PEDV Infection and Proinflammatory Cytokine Secretion via the HMGB1/TLR4-MAPK p38 Pathway

Viral infections are a major health problem; therefore, there is an urgent need for novel therapeutic strategies. Antivirals used to target proteins encoded by the viral genome usually enhance drug resistance generated by the virus. A potential solution may be drugs acting at host-based targets since viruses are dependent on numerous cellular proteins and phosphorylation events that are crucial during their life cycle. Repurposing existing kinase inhibitors as antiviral agents would help in the cost and effectiveness of the process, but this strategy usually does not provide much improvement, and specific medicinal chemistry programs are needed in the field. Anyway, extensive use of FDA-approved kinase inhibitors has been quite useful in deciphering the role of host kinases in viral infection. The present perspective aims to review the state of the art of kinase inhibitors that target viral infections in different development stages.

Kinase Inhibitors as Underexplored Antiviral Agents.

Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways.

Objective This study is aimed to reveal the possible mechanisms of artemisinin in the treatment of ulcerative colitis (UC) through bioinformatics analysis and experimental verification in UC model rats. Methods Firstly, we searched two microarray data of the Gene Expression Omnibus (GEO) database to explore the diﬀerentially expressed genes (DEGs) between UC samples and normal samples. Then, we selected DEGs for gene ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The acute UC model of rats was established by using 3.5% dextran sulfate sodium (DSS) for 10 days to verify the core pathway. Finally, we evaluated the therapeutic effect of artemisinin at the molecular level and used metabonomics to study the endogenous metabolites in the rat serum. Results We screened in the GEO database and selected two eligible microarray datasets, GSE36807 and GSE9452. We performed GO function and KEGG pathway enrichment analyses of DEGs and found that these DEGs were mainly enriched in the inflammatory response, immune response, and IL-17 and NF-κB signaling pathways. Finally, we verified the IL-17 signaling pathway and key cytokines, and ELISA and immunohistochemical results showed that artemisinin could downregulate the expression of proinflammatory cytokines such as IL-1β and IL-17 in the IL-17 signaling pathway and upregulate the expression of the anti-inflammatory cytokine PPAR-γ. Metabolomics analysis showed that 33 differential metabolites were identified in the artemisinin group (AG) compared to the model group (MG). Differential metabolites were mainly involved in alanine, aspartate, and glutamate metabolism and synthesis and degradation of ketone bodies. Conclusion In this study, we found that artemisinin can significantly inhibit the inflammatory response in UC rats and regulate metabolites and related metabolic pathways. This study provides a foundation for further research on the mechanism of artemisinin in the treatment of UC.

Artemisinin Alleviates Intestinal Inflammation and Metabolic Disturbance in Ulcerative Colitis Rats Induced by DSS

The development of high-efficiency economic photocatalyst for the production of hydrogen peroxide (H2O2) is of great significance for solar-to-fuel conversion. Bismuth oxychloride (BiOCl) shows giant potential for photocatalytic H2O2 production,...

The Enhanced Photocatalytic Properties for H2O2 Production over Bi/BiOCl Composite

COVID-19 has undergone multiple mutations, with the Omicron variant proving to be highly contagious and rapidly spreading across many countries. The United States was severely hit by the Omicron variant. However, it was still unclear how Omicron transferred across the United States. Here, we collected daily COVID-19 cases and deaths in each county from 1 December 2021 to 28 February 2022 as the Omicron wave. We adopted space-time scan statistics, the Hoover index, and trajectories of the epicenter to quantify spatiotemporal patterns of the Omicron wave of COVID-19. The results showed that the highest and earliest cluster was located in the Northeast. The Hoover index for both cases and deaths exhibited phases of rapid decline, slow decline, and relative stability, indicating a rapid spread of the Omicron wave across the country. The Hoover index for deaths was consistently higher than that for cases. The epicenter of cases and deaths shifted from the west to the east, then southwest. Nevertheless, cases were more widespread than deaths, with a lag in mortality data. This study uncovers the spatiotemporal patterns of Omicron transmission in the United States, and its underlying mechanisms deserve further exploration.

/pdf/spatiotemporal-patterns-of-the-omicron-wave-of-covid-19-in-2qqtazuo.pdf

Spatiotemporal Patterns of the Omicron Wave of COVID-19 in the United States

Exploring multifunctional photocatalysts with rational design and construction of unique transport channels is of great significance for the value-added chemicals production and environmental remediation. In this work, a novel 2D/1D/-2D RP/BP-MBWO dual heterostructure photocatalyst has been successfully synthesized by loading the in-situ grown 2D/1D RP/BP heterostructure on the 2D Bi2WO6 nanosheets. through simple ultrasonic agitation.Benefiting from this favourable interfacial and structural characteristics, the fabricated BP/RP-MBWO photocatalyst shows a sharply improved photocatalytic H2 and H2O2 evolution performance. Excitingly, the optimal of H2O2 production rate of the BP/RP-Bi2WO6 composites is as high as 622.5 μmol g−1 h−1 under visible light irradiation, which is approximately 15 times as that of pure MBWO. The hydrogen production performance of the complexes was significantly improved compared to the pure MBWO samples. When the BP/RP loading was 20 %, the prepared nanocomposites showed the highest photocatalytic hydrogen evolution efficiency with the hydrogen production rate of about 0.77 μmol ⋅ g−1 ⋅ h−1. This work is expected to offer a new inspiration for the rational design and construction of effcient photocatalyst systems toward solar energy capture and conversion. 

Construction of A Novel 2D/1D/‐2D RP/BP‐Bi
 2
 WO
 6
 Composite with
 In Situ
 Junction and Z‐scheme System for Enhanced Photocatalytic H
 2
 and H
 2
 O
 2
 Production

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Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways.

Artemisinin Alleviates Intestinal Inflammation and Metabolic Disturbance in Ulcerative Colitis Rats Induced by DSS

The Enhanced Photocatalytic Properties for H2O2 Production over Bi/BiOCl Composite

Spatiotemporal Patterns of the Omicron Wave of COVID-19 in the United States

Construction of A Novel 2D/1D/‐2D RP/BP‐Bi 2 WO 6 Composite with In Situ Junction and Z‐scheme System for Enhanced Photocatalytic H 2 and H 2 O 2 Production