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In vitro and in vivo effects of Pelargonium sidoides DC. root extract EPs^® 7630 and selected constituents against SARS-CoV-2 B.1, Delta AY.4/AY.117 and Omicron BA.2.

ABSTRACT: The occurrence of immune-evasive SARS-CoV-2 strains emphasizes the importance to search for broad-acting antiviral compounds. Our previous in vitro study showed that Pelargonium sidoides DC. root extract EPs^® 7630 has combined antiviral and immunomodulatory properties in SARS-CoV-2-infected human lung cells. Here we assessed in vivo effects of EPs^® 7630 in SARS-CoV-2-infected hamsters, and investigated properties of EPs^® 7630 and its functionally relevant constituents in context of phenotypically distinct SARS-CoV-2 variants. We show that EPs^® 7630 reduced viral load early in the course of infection and displayed significant immunomodulatory properties positively modulating disease progression in hamsters. In addition, we find that EPs^® 7630 differentially inhibits SARS-CoV-2 variants in nasal and bronchial human airway epithelial cells. Antiviral effects were more pronounced against Omicron BA.2 compared to B.1 and Delta, the latter two preferring TMPRSS2-mediated fusion with the plasma membrane for cell entry instead of receptor-mediated low pH-dependent endocytosis. By using SARS-CoV-2 Spike VSV-based pseudo particles (VSVpp), we confirm higher EPs^® 7630 activity against Omicron Spike-VSVpp, which seems independent of the serine protease TMPRSS2, suggesting that EPs^® 7630 targets endosomal entry. We identify at least two molecular constituents of EPs^® 7630, i.e., (-)-epigallocatechin and taxifolin with antiviral effects on SARS-CoV-2 replication and cell entry. In summary, our study shows that EPs^® 7630 ameliorates disease outcome in SARS-CoV-2-infected hamsters and has enhanced activity against Omicron, apparently by limiting late endosomal SARS-CoV-2 entry.

SUBMITTER: Emanuel J

PROVIDER: S-EPMC10410074 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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In vitro and in vivo effects of Pelargonium sidoides DC. root extract EPs® 7630 and selected constituents against SARS-CoV-2 B.1, Delta AY.4/AY.117 and Omicron BA.2.

Emanuel Jackson J Papies Jan J Galander Celine C Adler Julia M JM Heinemann Nicolas N Eschke Kathrin K Merz Sophie S Pischon Hannah H Rose Ruben R Krumbholz Andi A Kulić Žarko Ž Lehner Martin D MD Trimpert Jakob J Müller Marcel A MA

Frontiers in pharmacology 20230726

The occurrence of immune-evasive SARS-CoV-2 strains emphasizes the importance to search for broad-acting antiviral compounds. Our previous in vitro study showed that Pelargonium sidoides DC. root extract EPs® 7630 has combined antiviral and immunomodulatory properties in SARS-CoV-2-infected human lung cells. Here we assessed in vivo effects of EPs® 7630 in SARS-CoV-2-infected hamsters, and investigated properties of EPs® 7630 and its function ...[more]

PMID: 37564181

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Project description:Treatment options for COVID-19 are currently limited. Drugs reducing both viral loads and SARS-CoV-2-induced inflammatory responses would be ideal candidates for COVID-19 therapeutics. Previous in vitro and clinical studies suggest that the proprietary Pelargonium sidoides DC. root extract EPs 7630 has antiviral and immunomodulatory properties, limiting symptom severity and disease duration of infections with several upper respiratory viruses. Here we assessed if EPs 7630 affects SARS-CoV-2 propagation and the innate immune response in the human lung cell line Calu-3. In direct comparison to other highly pathogenic CoV (SARS-CoV, MERS-CoV), SARS-CoV-2 growth was most efficiently inhibited at a non-toxic concentration with an IC50 of 1.61 μg/ml. Particularly, the cellular entry step of SARS-CoV-2 was significantly reduced by EPs 7630 pretreatment (10-100 μg/ml) as shown by spike protein-carrying pseudovirus particles and infectious SARS-CoV-2. Using sequential ultrafiltration, EPs 7630 was separated into fractions containing either prodelphinidins of different oligomerization degrees or small molecule constituents like benzopyranones and purine derivatives. Prodelphinidins with a low oligomerization degree and small molecule constituents were most efficient in inhibiting SARS-CoV-2 entry already at 10 μg/ml and had comparable effects on immune gene regulation as EPs 7630. Downregulation of multiple pro-inflammatory genes (CCL5, IL6, IL1B) was accompanied by upregulation of anti-inflammatory TNFAIP3 at 48 h post-infection. At high concentrations (100 μg/ml) moderately oligomerized prodelphinidins reduced SARS-CoV-2 propagation most efficiently and exhibited pronounced immune gene modulation. Assessment of cytokine secretion in EPs 7630-treated and SARS-CoV-2-coinfected Calu-3 cells showed that pro-inflammatory cytokines IL-1β and IL-6 were elevated whereas multiple other COVID-19-associated cytokines (IL-8, IL-13, TNF-α), chemokines (CXCL9, CXCL10), and growth factors (PDGF, VEGF-A, CD40L) were significantly reduced by EPs 7630. SARS-CoV-2 entry inhibition and the differential immunomodulatory functions of EPs 7630 against SARS-CoV-2 encourage further in vivo studies.

Project description:BackgroundThe efficacy and tolerability of Pelargonium sidoides DC. root extract EPs 7630 in children with acute bronchitis (AB) have been widely demonstrated. We investigated the safety and tolerability of a syrup formulation and an oral solution in pre-school children.MethodsIn an open-label, randomized clinical trial (EudraCT number 2011-002652-14), children aged 1-5 years suffering from AB received EPs 7630 syrup or solution for 7 days. Safety was assessed by frequency, severity, and nature of adverse events (AE), vital signs, and laboratory values. Outcome measures for evaluating the health status were the intensity of coughing, pulmonary rales, and dyspnea, measured by the short version of the Bronchitis Severity Scale (BSS-ped), further symptoms of the respiratory infection, general health status according to the Integrative Medicine Outcomes Scale (IMOS), and satisfaction with treatment according to the Integrative Medicine Patient Satisfaction Scale (IMPSS).Results591 children were randomized and treated with syrup (n = 403) or solution (n = 188) for 7 days. In both treatment groups, the number of adverse events was similarly low and revealed no safety concerns. The most frequently observed events were infections (syrup: 7.2%; solution: 7.4%) or gastrointestinal disorders (syrup: 2.7%; solution: 3.2%). After one week's treatment, more than 90% of the children experienced an improvement or remission of the symptoms of the BSS-ped. Further respiratory symptoms decreased similarly in both groups. At Day 7, more than 80% of the whole study population had completely recovered or showed a major improvement as assessed by the investigator and the proxy, respectively. Parents were "very satisfied" or "satisfied" with the treatment in 86.1% of patients in the combined syrup and solution group.ConclusionBoth pharmaceutical forms, EPs 7630 syrup and oral solution, were shown to be equally safe and well tolerated in pre-school children suffering from AB. Improvement of health status and of complaints were similar in both groups.

Dataset Information

In vitro and in vivo effects of Pelargonium sidoides DC. root extract EPs^® 7630 and selected constituents against SARS-CoV-2 B.1, Delta AY.4/AY.117 and Omicron BA.2.

Publications

<i>In vitro</i> and <i>in vivo</i> effects of <i>Pelargonium sidoides DC.</i> root extract EPs<sup>®</sup> 7630 and selected constituents against SARS-CoV-2 B.1, Delta AY.4/AY.117 and Omicron BA.2.

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