Androgen receptor, a possible anti-infective therapy target and a potent immune respondent in SARS-CoV-2 spike binding: a computational approach.

BACKGROUND: Although androgen in gender disparity of COVID-19 has been implied, no direct link has been provided. RESEARCH DESIGN AND METHODS: Here, we applied AlphaFold multimer, network and single cells database analyses to highlight specificity of Androgen receptor (AR) against spike receptor binding protein (RBD) of SARS-CoV-2. RESULTS: LXXL motifs in spike RBD are essential for AR binding. RBD LXXA mutation complex with the AR depicting slightly reduced binding energy, as LXXLL motif usually mediates nuclear receptor binding to coregulators. Moreover, AR preferred to bind a LYRL motif in specificity and interaction interface, and showed reduced affinity against Omicron compared to other variants (alpha, beta, gamma, and delta). Importantly, RBD LYRL motif is a conserved antigenic epitope (9 residues) for T-cell response. Network analysis of AR-related genes against COVID-19 database showed T-cell signaling regulation, and CD8+ T-cell spatial location in AR+ single cells, which is consistent with the AR binding motif LYRL in epitope function. CONCLUSIONS: We provided the potent mechanisms of AR binding to RBD linking to immune response and vaccination shift. AR could be an anti-infective therapy target for anti-Omicron new lineages.

Lucidenic acid A inhibits the binding of hACE2 receptor with spike protein to prevent SARS-CoV-2 invasion.

High infection caused by mutations of SARS-CoV-2 calls for new prevention strategy. Ganoderma lucidum known as a superior immunoenhancer exhibits various antiviral effects, whether it can resist SARS-CoV-2 remains unclear. Herein, virtual screening combined with in vitro hACE2 inhibition assays were used to investigate its anti SARS-CoV-2 effect. Potential 54 active components, 80 core targets and 20 crucial pathways were identified by the component-target-pathway network. The binding characters of these components to hACE2 and its complexes with spike protein including omicron variant was analyzed by molecular docking. Lucidenic acid A was selected as the top molecule with high affinity to all receptors by forming hydrogen bonds. Molecular dynamics simulation showed it had good binding stability with the receptor proteins. Finally, in vitro FRET test demonstrated it inhibited the hACE2 activity with IC50 2 µmol/mL. Therefore, lucidenic acid A can prevent the virus invasion by blocking hACE2 binding with SARS-CoV-2.

Honghua extract mediated potent inhibition of COVID-19 host cell pathways.

Honghua (Carthami flos) and Xihonghua (Croci stigma) have been used in anti-COVID-19 as Traditional Chinese Medicine, but the mechanism is unclear. In this study, we applied network pharmacology by analysis of active compounds and compound-targets networks, enzyme kinetics assay, signaling pathway analysis and investigated the potential mechanisms of anti-COVID-19. We found that both herbs act on signaling including kinases, response to inflammation and virus. Moreover, crocin likely has an antiviral effect due to its high affinity towards the human ACE2 receptor by simulation. The extract of Honghua and Xihonghua exhibited nanozyme/herbzyme activity of alkaline phosphatase, with distinct fluorescence. Thus, our data suggest the great potential of Honghua in the development of anti-COVID-19 agents.

Rhizoma polygonati from Mount Tai: Nutritional value and usefulness as a traditional Chinese medicine, source of herbzyme, and potential remediating agent for COVID-19 and chronic and hidden hunger

Recently, traditional Chinese medicine-based treatment has succeeded in fighting coronavirus disease 2019 (COVID-19), and Rhizoma polygonati (Huangjing) has been one of the recommended components. Its processed products play antidiabetic, antiviral, antitumor, antioxidation, antifatigue, antiaging, and immune enhancement roles. The climate in Mount Tai is mild, and the dense forest is suitable for the growth of Rhizome polygonati, which has gradually evolved into a unique specie. Considering the important medicinal value and pleasant taste of Mount Tai-Rhizoma polygonati, various healthy and functional food products, controlled by quality markers with anti-COVID-19 potential, as well as emergency foods can be developed. The study aimed to review current evidence on the nutritional value of Rhizoma polygonati from Mount Tai and its usefulness as a traditional Chinese medicine, source of herbzyme, and potential remediating agent for COVID-19 and food shortage. Most recent findings regarding herbal nanomedicine have revealed that nanoscale chemical compounds are potentially efficient in drug delivery or nanozyme catalysis upon bioprocessing. Nanoflower structure is found in processed Rhizoma polygonati by self-assembly and has wide application in enzymatic events, particularly nanoscale herbzyme. The novel findings regarding Mount Tai-Rhizoma polygonati could enhance its novel applications in chronic and hidden hunger, clinical nanomedicine, and as an anti-COVID-19 agent.

Omicron N501Y mutation among SARS-CoV-2 lineages: Insilico analysis of potent binding to tyrosine kinase and hypothetical repurposed medicine.

Variants of SARS-CoV-2 lineages including the most recently circulated Omicron, and previous pandemic B.1.351, B.1.1.7, which have been public concerns, contain a N501Y mutation located in the spike receptor binding domain. However, the potential interactions with host cells linking N501Y mutation to pathogenic relevance remain elusive. Recently, we and others report that kinases such as PI3K/AKT signaling are essential in SARS-CoV-2 entry. Here we analyzed the predicted potential kinases interacting with the mutation. Bioinformatics tools including structure-prediction based molecular docking analysis were applied. We found kinases such as EGFR might potentially act as new factors involving the N501Y mutation binding through possible phosphorylation at Y501 and enhanced affinity in certain variants. To our surprise, the Omicron receptor binding domain harboring N501Y mutation did not enhance binding to EGFR which might be due to the mutations of charged polar to uncharged polar side chains located on the interaction interfaces. Similarly, potent gains of phosphorylation in B.1.351 and B.1.1.7 by mutations were predicted and interaction networks were analyzed with enrichment of pathways. Given kinases might be elevated in cancer patients, the N501Y mutation containing lineages may be possibly much more infectious and additional care for cancer management might be taken into consideration by precision prevention, therapy or recovery.

Capivasertib restricts SARS-CoV-2 cellular entry: a potential clinical application for COVID-19.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to more than 150 million infections and about 3.1 million deaths up to date. Currently, drugs screened are urgently aiming to block the infection of SARS-CoV-2. Here, we explored the interaction networks of kinase and COVID-19 crosstalk, and identified phosphoinositide 3-kinase (PI3K)/AKT pathway as the most important kinase signal pathway involving COVID-19. Further, we found a PI3K/AKT signal pathway inhibitor capivasertib restricted the entry of SARS-CoV-2 into cells under non-cytotoxic concentrations. Lastly, the signal axis PI3K/AKT/FYVE finger-containing phosphoinositide kinase (PIKfyve)/PtdIns(3,5)P2 was revealed to play a key role during the cellular entry of viruses including SARS-CoV-2, possibly providing potential antiviral targets. Altogether, our study suggests that the PI3K/AKT kinase inhibitor drugs may be a promising anti-SARS-CoV-2 strategy for clinical application, especially for managing cancer patients with COVID-19 in the pandemic era.

Dataset of potential Rhizoma Polygonati compound-druggable targets and partial pharmacokinetics for treatment of COVID-19.

Rhizoma Polygonati (Chinese name as , pinyin as huangjing), as medicine and food homology of Traditional Chinese Medicine, has been recently applied for the complex prescriptions of alternative medicine for treatment of COVID-19 but the mechanisms are largely unclear. Here using public database search and filtering the potential chemical compound based drug targets with COVID-19 targets mapped, the list of data were provided and suggested pharmacokinetic tolerating dose of selected natural compounds were further collected from database. The data provided is the supplementary as a reference showing the intersections of Rhizoma Polygonati druggable targets of lists from current database and potentially related ones targeting COVID-19.

Potential compound from herbal food of Rhizoma Polygonati for treatment of COVID-19 analyzed by network pharmacology: Viral and cancer signaling mechanisms.

Rhizoma Polygonati (huangjing in Chinese, ) is a medicine food homology herb used as a component of traditional Chinese medicine treating COVID-19 in the current pandemic emergency in China but the mechanisms remain elusive. Here using TCMSP and Swiss Target Prediction databases to sort out the potential targets of the main chemical components and GenCLiP3, NCBI, and GeneCard databases to search for COVID-19 related targets, the chemical compound-target-pathway network was analyzed. Each component was molecularly docked with host cell target angiotensin converting enzyme II, SARS-CoV-2 targets Spike protein, RNA-dependent RNA polymerase, or 3CL hydrolase. Our results showed a higher affinity of the compound diosgenin and (+)-Syringaresinol-O-beta-D-glucoside binding to the three SARS-CoV-2 proteins compared to the other compounds tested. Thus, our data suggest that potential compounds in Rhizoma Polygonati may act on different targets with viral and cancer related signaling and have a great potential in treatment of COVID-19.