Antiviral potential of garlic (Allium sativum) and its organosulfur compounds: A systematic update of pre-clinical and clinical data.

BACKGROUND: Garlic (Allium sativum L.) is a common herb consumed worldwide as functional food and traditional remedy for the prevention of infectious diseases since ancient time. Garlic and its active organosulfur compounds (OSCs) have been reported to alleviate a number of viral infections in pre-clinical and clinical investigations. However, so far no systematic review on its antiviral effects and the underlying molecular mechanisms exists. SCOPE AND APPROACH: The aim of this review is to systematically summarize pre-clinical and clinical investigations on antiviral effects of garlic and its OSCs as well as to further analyse recent findings on the mechanisms that underpin these antiviral actions. PubMed, Cochrane library, Google Scholar and Science Direct databases were searched and articles up to June 2020 were included in this review. KEY FINDINGS AND CONCLUSIONS: Pre-clinical data demonstrated that garlic and its OSCs have potential antiviral activity against different human, animal and plant pathogenic viruses through blocking viral entry into host cells, inhibiting viral RNA polymerase, reverse transcriptase, DNA synthesis and immediate-early gene 1(IEG1) transcription, as well as through downregulating the extracellular-signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling pathway. The alleviation of viral infection was also shown to link with immunomodulatory effects of garlic and its OSCs. Clinical studies further demonstrated a prophylactic effect of garlic in the prevention of widespread viral infections in humans through enhancing the immune response. This review highlights that garlic possesses significant antiviral activity and can be used prophylactically in the prevention of viral infections.

Mollisolactones A and B, novel dinormonoterpenes from the soft coral Sinularia mollis.

Two novel dinormonoterpenes, designated as mollisolactones A and B, were discovered from the soft coral Sinularia mollis on the basis of a chromatographic and NMR spectroscopy-based fractionation. Their structures were solved through analysis of comprehensive 1D and 2D NMR spectroscopic data and HRESIMS experiments. The biological activities of the obtained metabolites were evaluated for cytotoxicity against A-459 (human lung carcinoma), HT-29 (human colon adenocarcinoma), and P-388 (mouse lymphocytic leukemia) cancer cell lines as well as antiviral activity against HCMV (human cytomegalovirus).

Sandensone A, a novel sesquiterpenoid from the Formosan soft coral Sinularia sandensis.

A chromatographic and NMR spectroscopy-based fractionation on the acetone extracts of the soft coral Sinularia sandensis led to the isolation of a novel sesquiterpenoid, sandensone A (1). The structure of 1 was elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HRESIMS spectrometry. The absolute configuration at C-12 of 1 was determined as R using a modified Mosher's method. The cytotoxicity against A549 (human lung carcinoma), HT-29 (human colon adenocarcinoma), and P-388 (mouse lymphocytic leukemia) cancer cell lines as well as antiviral activity against HCMV (human cytomegalovirus) were evaluated in vitro.

Sinugyrosanolide A, an unprecedented C-4 norcembranoid, from the Formosan soft coral Sinularia gyrosa.

Chemical investigations on the acetone extract of the Formosan soft coral Sinularia gyrosa have obtained a novel C-4 norcembranoid possessing an unprecedented tricyclo[9.3.0.0(3,8)]tetradecane skeleton, namely sinugyrosanolide A. The NMR spectroscopic data of the novel norcembranoid were completely assigned by using a combination of 2D NMR experiments including (1)H-(1)H COSY, HSQC, HMBC, and NOESY. The cytotoxicities, anti-HCMV (human cytomegalovirus) endonuclease activities and antibacterial activities were evaluated in vitro. It showed moderate cytotoxicity against P-388 (mouse lymphocytic leukemia) cancer cell line with an EC50 of 11.8µM.

Therapeutic targeting of HCMV-encoded chemokine receptor US28: Progress and challenges.

The pervasive human cytomegalovirus (HCMV) causes significant morbidity in immunocompromised individuals. Treatment using the current standard-of-care (SOC) is limited by severe toxic adverse effects and anti-viral resistance development. Furthermore, they only affect HCMV in its lytic phase, meaning viral disease is not preventable as latent infection cannot be treated and the viral reservoirs persist. The viral chemokine receptor (vCKR) US28 encoded by HCMV has received much attention in recent years. This broad-spectrum receptor has proven to be a desirable target for development of novel therapeutics through exploitation of its ability to internalize and its role in maintaining latency. Importantly, it is expressed on the surface of infected cells during both lytic and latent infection. US28-targeting small molecules, single-domain antibodies, and fusion toxin proteins have been developed for different treatment strategies, e.g. forcing reactivation of latent virus or using internalization of US28 as a toxin shuttle to kill infected cells. These strategies show promise for providing ways to eliminate latent viral reservoirs and prevent HCMV disease in vulnerable patients. Here, we discuss the progress and challenges of targeting US28 to treat HCMV infection and its associated diseases.

Promising Role of Emodin as Therapeutics to Against Viral Infections.

Emodin is an anthraquinone derivative that is widely present in natural plants and has a wide spectrum of pharmacological effects, such as antibacterial, anti-inflammatory, anti-fibrotic and anticancer and so on. Through reviewing studies on antiviral effect of emodin in the past decades, we found that emodin exhibits ability of inhibiting the infection and replication of more than 10 viruses in vitro and in vivo, including herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), coxsackievirus B (CVB), hepatitis B virus (HBV), influenza A virus (IAV), SARS-CoV, viral haemorrhagic septicaemia rhabdovirus (VHSV), enterovirus 71 (EV71), dengue virus serotype 2 (DENV-2) and Zika virus (ZIKV). Therefore, this review aims to summarize the antiviral effect of emodin, in order to provide reference and hopes to support the further investigations.

The human cytomegalovirus decathlon: Ten critical replication events provide opportunities for restriction.

Human cytomegalovirus (HCMV) is a ubiquitous human pathogen that can cause severe disease in immunocompromised individuals, transplant recipients, and to the developing foetus during pregnancy. There is no protective vaccine currently available, and with only a limited number of antiviral drug options, resistant strains are constantly emerging. Successful completion of HCMV replication is an elegant feat from a molecular perspective, with both host and viral processes required at various stages. Remarkably, HCMV and other herpesviruses have protracted replication cycles, large genomes, complex virion structure and complicated nuclear and cytoplasmic replication events. In this review, we outline the 10 essential stages the virus must navigate to successfully complete replication. As each individual event along the replication continuum poses as a potential barrier for restriction, these essential checkpoints represent potential targets for antiviral development.

Virus-host interaction analysis in colorectal cancer identifies core virus network signature and small molecules.

Colorectal cancer (CRC) is a significant contributor to cancer-related deaths caused by an unhealthy lifestyle. Multiple studies reveal that viruses are involved in colorectal tumorigenesis. The viruses such as Human Cytomegalovirus (HCMV), Human papillomaviruses (HPV16 & HPV18), and John Cunningham virus (JCV) are known to cause colorectal cancer. The molecular mechanisms of cancer genesis and maintenance shared by these viruses remain unclear. We analysed the virus-host networks and connected them with colorectal cancer proteome datasets and extracted the core shared interactions in the virus-host CRC network. Our network topology analysis identified prominent virus proteins RL6 (HCMV), VE6 (HPV16 and HPV18), and Large T antigen (JCV). Sequence analysis uncovered short linear motifs (SLiMs) in each viral target. We used these targets to identify the antiviral drugs through a structure-based virtual screening approach. This analysis highlighted that temsavir, pimodivir, famotine, and bictegravir bind to each virus protein target, respectively. We also assessed the effect of drug binding using molecular dynamic simulations, which shed light on the modulatory effect of drug molecules on SLiM regions in viral targets. Hence, our systematic screening of virus-host networks revealed viral targets, which could be crucial for cancer therapy.

Broad and Efficient Activation of Memory CD4+ T Cells by Novel HAdV- and HCMV-Derived Peptide Pools.

Reactivation of Human Cytomegalovirus (HCMV) and Human Adenovirus (HAdV) in immunocompromised patients following stem cell transplantation (SCT) or solid organ transplantation (SOT) is associated with high morbidity and mortality. The adoptive transfer of virus-specific CD8+ and CD4+ T cells has been shown to re-establish the antiviral T-cell response and improve clinical outcome. The viral load in immunocompromised patients can efficiently be reduced solely by the infusion of virus-specific CD4+ T cells. The identification of CD4+ T-cell epitopes has mainly focused on a limited number of viral proteins that were characterized as immunodominant. Here, we used in silico prediction to determine promiscuous CD4+ T-cell epitopes from the entire proteomes of HCMV and HAdV. Immunogenicity testing with enzyme-linked immuno spot (ELISpot) assays and intracellular cytokine staining (ICS) revealed numerous novel CD4+ T-cell epitopes derived from a broad spectrum of viral antigens. We identified 17 novel HCMV-derived and seven novel HAdV-derived CD4+ T-cell epitopes that were recognized by > 50% of the assessed peripheral blood mononuclear cell (PBMC) samples. The newly identified epitopes were pooled with previously published, retested epitopes to stimulate virus-specific memory T cells in PBMCs from numerous randomly selected blood donors. Our peptide pools induced strong IFNγ secretion in 46 out of 48 (HCMV) and 31 out of 31 (HAdV) PBMC cultures. In conclusion, we applied an efficient method to screen large viral proteomes for promiscuous CD4+ T-cell epitopes to improve the detection and isolation of virus-specific T cells in a clinical setting.

Modelling of pathogen-host systems using deeper ORF annotations and transcriptomics to inform proteomics analyses.

The Zika virus is a flavivirus that can cause fulminant outbreaks and lead to Guillain-Barré syndrome, microcephaly and fetal demise. Like other flaviviruses, the Zika virus is transmitted by mosquitoes and provokes neurological disorders. Despite its risk to public health, no antiviral nor vaccine are currently available. In the recent years, several studies have set to identify human host proteins interacting with Zika viral proteins to better understand its pathogenicity. Yet these studies used standard human protein sequence databases. Such databases rely on genome annotations, which enforce a minimal open reading frame (ORF) length criterion. An ever-increasing number of studies have demonstrated the shortcomings of such annotation, which overlooks thousands of functional ORFs. Here we show that the use of a customized database including currently non-annotated proteins led to the identification of 4 alternative proteins as interactors of the viral capsid and NS4A proteins. Furthermore, 12 alternative proteins were identified in the proteome profiling of Zika infected monocytes, one of which was significantly up-regulated. This study presents a computational framework for the re-analysis of proteomics datasets to better investigate the viral-host protein interplays upon infection with the Zika virus.

A two-stage computational approach to predict novel ligands for a chemosensory receptor.

Olfactory receptor (OR) 1A2 is the member of largest superfamily of G protein-coupled receptors (GPCRs). OR1A2 is an ectopically expressed receptor with only 13 known ligands, implicated in reducing hepatocellular carcinoma progression, with enormous therapeutic potential. We have developed a two-stage screening approach to identify novel putative ligands of OR1A2. We first used a pharmacophore model based on atomic property field (APF) to virtually screen a library of 5942 human metabolites. We then carried out structure-based virtual screening (SBVS) for predicting the potential agonists, based on a 3D homology model of OR1A2. This model was developed using a biophysical approach for template selection, based on multiple parameters including hydrophobicity correspondence, applied to the complete set of available GPCR structures to pick the most appropriate template. Finally, the membrane-embedded 3D model was refined by molecular dynamics (MD) simulations in both the apo and holo forms. The refined model in the apo form was selected for SBVS. Four novel small molecules were identified as strong binders to this olfactory receptor on the basis of computed binding energies.

Can network pharmacology identify the anti-virus and anti- inflammatory activities of Shuanghuanglian oral liquid used in Chinese medicine for respiratory tract infection?

INTRODUCTION: Shuanghuanglian (SHL) oral liquid is a well-known traditional Chinese medicine preparation administered for respiratory tract infections in China. However, the underlying pharmacological mechanisms remain unclear. The present study aims to determine the potential pharmacological mechanisms of SHL oral liquid based on network pharmacology. METHODS: Network pharmacology-based strategy including collection and analysis of putative compounds and target genes, network construction, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Gene Ontology (GO) enrichment, identification of key compounds and target genes, and molecule docking was performed in this study. RESULTS: A total of 82 bioactive compounds and 226 putative target genes of SHL oral liquid were collected. Of note, 28 hub target genes including 4 major hub target genes: estrogen receptor 1 (ESR1), nuclear receptor coactivator 2 (NCOA2), nuclear receptor coactivator 1 (NCOA1), androgen receptor (AR) and 5 key compounds (quercetin, luteolin, baicalein, kaempferol and wogonin) were identified based on network analysis. The hub target genes mainly enriched in pathways including PI3K-Akt signaling pathway, human cytomegalovirus infection, and human papillomavirus infection, which could be the underlying pharmacological mechanisms of SHL oral liquid for treating diseases. Moreover, the key compounds had great molecule docking binding affinity with the major hub target genes. CONCLUSION: Using network pharmacology analysis, SHL oral liquid was found to contain anti-virus, anti-inflammatory, and "multi-compounds and multi-targets" with therapeutic actions. These findings may provide a valuable direction for further clinical application and research.

Subversion of Immune Response by Human Cytomegalovirus.

Human cytomegalovirus (HCMV) is the most common cause of congenital infections and is an important pathogen in immunocompromised individuals. Despite a robust host immune system, HCMV able to replicate, evade host defenses, establish latency for life. A significant portion of HCMV genome dedicated to encode gene products for modulation of host immune response. Growing number of HCMV gene products are being recognized to play role in immune evasion. Information on viral immune evasion mechanisms by which HCMV persists in host will be useful in devising antiviral intervention strategies and development of new vaccines. This minireview provides a brief overview of immune evasion strategy adapted by HCMV by utilizing its gene products in modulation of host immune response.

Discordant humoral and cellular immune responses to Cytomegalovirus (CMV) in glioblastoma patients whose tumors are positive for CMV.

Background. Glioblastoma (GBM) is the most common malignant brain tumor in adults and is nearly always fatal. Emerging evidence suggests that human Cytomegalovirus (HCMV) is present in 90-100% of GBMs and that add-on antiviral treatment for HCMV show promise to improve survival. Methods. In a randomized, placebo-controlled trial of valganciclovir in 42 GBM patients, blood samples were collected for analyses of HCMV DNA, RNA, reactivity against HCMV peptides, IgG, and IgM at baseline and at 3, 12, and 24 weeks of treatment. Results. All 42 tumors were positive for HCMV protein. All patients examined had at least one blood sample positive for HCMV DNA, 63% were HCMV RNA positive, and 21% were IgM positive. However, 29% of GBM patients were IgG negative for HCMV. Five of these samples were positive in an enzyme-linked immunosorbent assay (ELISA) that used antigens derived from a clinical isolate. Blood T cells from 11 of 13 (85%) HCMV IgG-negative GBM patients reacted against HCMV peptides. Valganciclovir did not affect IgG titers, DNA, or RNA levels of the HCMV immediate early (HCMV IE) gene in blood. Conclusion. In GBM patients, HCMV activity is higher than in healthy controls and serology is a poor test to define previous or active HCMV infection in these patients.