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1.
Phytochem Rev ; 21(3): 725-764, 2022.
Article in English | MEDLINE | ID: covidwho-1384539

ABSTRACT

Flavaglines are formed by cycloaddition of a flavonoid nucleus with a cinnamic acid moiety representing a typical chemical character of the genus Aglaia of the family Meliaceae. Based on biosynthetic considerations 148 derivatives are grouped together into three skeletal types representing 77 cyclopenta[b]benzofurans, 61 cyclopenta[bc]benzopyrans, and 10 benzo[b]oxepines. Apart from different hydroxy, methoxy, and methylenedioxy groups of the aromatic rings, important structural variation is created by different substitutions and stereochemistries of the central cyclopentane ring. Putrescine-derived bisamides constitute important building blocks occurring as cyclic 2-aminopyrrolidines or in an open-chained form, and are involved in the formation of pyrimidinone flavaglines. Regarding the central role of cinnamic acid in the formation of the basic skeleton, rocagloic acid represents a biosynthetic precursor from which aglafoline- and rocaglamide-type cyclopentabenzofurans can be derived, while those of the rocaglaol-type are the result of decarboxylation. Broad-based comparison revealed characteristic substitution trends which contribute as chemical markers to natural delimitation and grouping of taxonomically problematic Aglaia species. A wide variety of biological activities ranges from insecticidal, antifungal, antiprotozoal, and anti-inflammatory properties, especially to pronounced anticancer and antiviral activities. The high insecticidal activity of flavaglines is comparable with that of the well-known natural insecticide azadirachtin. Comparative feeding experiments informed about structure-activity relationships and exhibited different substitutions of the cyclopentane ring essential for insecticidal activity. Parallel studies on the antiproliferative activity of flavaglines in various tumor cell lines revealed similar structural prerequisites that let expect corresponding molecular mechanisms. An important structural modification with very high cytotoxic potency was found in the benzofuran silvestrol characterized by an unusual dioxanyloxy subunit. It possessed comparable cytotoxicity to that of the natural anticancer compounds paclitaxel (Taxol®) and camptothecin without effecting normal cells. The primary effect was the inhibition of protein synthesis by binding to the translation initiation factor eIF4A, an ATP-dependent DEAD-box RNA helicase. Flavaglines were also shown to bind to prohibitins (PHB) responsible for regulation of important signaling pathways, and to inhibit the transcriptional factor HSF1 deeply involved in metabolic programming, survival, and proliferation of cancer cells. Flavaglines were shown to be not only promising anticancer agents but gained now also high expectations as agents against emerging RNA viruses like SARS-CoV-2. Targeting the helicase eIF4A with flavaglines was recently described as pan-viral strategy for minimizing the impact of future RNA virus pandemics.

2.
Antiviral Res ; 186: 105012, 2021 02.
Article in English | MEDLINE | ID: covidwho-1064809

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, a severe respiratory disease with varying clinical presentations and outcomes, and responsible for a major pandemic that started in early 2020. With no vaccines or effective antiviral treatments available, the quest for novel therapeutic solutions remains an urgent priority. Rocaglates, a class of plant-derived cyclopenta[b]benzofurans, exhibit broad-spectrum antiviral activity against multiple RNA viruses including coronaviruses. Specifically, rocaglates inhibit eukaryotic initiation factor 4A (eIF4A)-dependent mRNA translation initiation, resulting in strongly reduced viral RNA translation. Here, we assessed the antiviral activity of the synthetic rocaglate CR-31-B (-) against SARS-CoV-2 using both in vitro and ex vivo cell culture models. In Vero E6 cells, CR-31-B (-) inhibited SARS-CoV-2 replication with an EC50 of ~1.8 nM. In primary human airway epithelial cells, CR-31-B (-) reduced viral titers to undetectable levels at a concentration of 100 nM. Reduced virus reproduction was accompanied by substantially reduced viral protein accumulation and replication/transcription complex formation. The data reveal a potent anti-SARS-CoV-2 activity by CR-31-B (-), corroborating previous results obtained for other coronaviruses and supporting the idea that rocaglates may be used in first-line antiviral intervention strategies against novel and emerging RNA virus outbreaks.


Subject(s)
Antiviral Agents/pharmacology , Benzofurans/pharmacology , Hydroxamic Acids/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Benzofurans/chemistry , Bronchi/virology , Cells, Cultured , Chlorocebus aethiops , Eukaryotic Initiation Factor-4A/antagonists & inhibitors , Humans , Hydroxamic Acids/chemistry , Respiratory Mucosa/virology , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Vero Cells , Viral Load/drug effects , Viral Replication Compartments/drug effects
3.
Intensive Care Med Exp ; 8(1): 75, 2020 Dec 11.
Article in English | MEDLINE | ID: covidwho-970766

ABSTRACT

BACKGROUND: COVID19 is caused by the SARS-CoV-2 virus and has been associated with severe inflammation leading to organ dysfunction and mortality. Our aim was to profile the transcriptome in leukocytes from critically ill patients positive for COVID19 compared to those negative for COVID19 to better understand the COVID19-associated host response. For these studies, all patients admitted to our tertiary care intensive care unit (ICU) suspected of being infected with SARS-CoV-2, using standardized hospital screening methodologies, had blood samples collected at the time of admission to the ICU. Transcriptome profiling of leukocytes via ribonucleic acid sequencing (RNAseq) was then performed and differentially expressed genes as well as significantly enriched gene sets were identified. RESULTS: We enrolled seven COVID19 + (PCR positive, 2 SARS-CoV-2 genes) and seven age- and sex-matched COVID19- (PCR negative) control ICU patients. Cohorts were well-balanced with the exception that COVID19- patients had significantly higher total white blood cell counts and circulating neutrophils and COVID19 + patients were more likely to suffer bilateral pneumonia. The mortality rate for this cohort of COVID19 + ICU patients was 29%. As indicated by both single-gene based and gene set (GSEA) approaches, the major disease-specific transcriptional responses of leukocytes in critically ill COVID19 + ICU patients were: (i) a robust overrepresentation of interferon-related gene expression; (ii) a marked decrease in the transcriptional level of genes contributing to general protein synthesis and bioenergy metabolism; and (iii) the dysregulated expression of genes associated with coagulation, platelet function, complement activation, and tumour necrosis factor/interleukin 6 signalling. CONCLUSIONS: Our findings demonstrate that critically ill COVID19 + patients on day 1 of admission to the ICU display a unique leukocyte transcriptional profile that distinguishes them from COVID19- patients, providing guidance for future targeted studies exploring novel prognostic and therapeutic aspects of COVID19.

4.
Clin Sci (Lond) ; 134(19): 2645-2664, 2020 10 16.
Article in English | MEDLINE | ID: covidwho-872746

ABSTRACT

The virulence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the aggressive nature of the disease has transformed the universal pace of research in the desperate attempt to seek effective therapies to halt the morbidity and mortality of this pandemic. The rapid sequencing of the SARS-CoV-2 virus facilitated identification of the receptor for angiotensin converting enzyme 2 (ACE2) as the high affinity binding site that allows virus endocytosis. Parallel evidence that coronavirus disease 2019 (COVID-19) disease evolution shows greater lethality in patients with antecedent cardiovascular disease, diabetes, or even obesity questioned the potential unfavorable contribution of angiotensin converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers as facilitators of adverse outcomes due to the ability of these therapies to augment the transcription of Ace2 with consequent increase in protein formation and enzymatic activity. We review, here, the specific studies that support a role of these agents in altering the expression and activity of ACE2 and underscore that the robustness of the experimental data is associated with weak clinical long-term studies of the existence of a similar regulation of tissue or plasma ACE2 in human subjects.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/drug effects , Pneumonia, Viral/virology , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/enzymology , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/enzymology , SARS-CoV-2 , Time Factors
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