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.