Spumigins produced by Nodularia spumigena are natural serine protease inhibitors with anti-SARS-CoV-2 activity.

COVID-19, caused by SARS-CoV-2, has led to significant morbidity and mortality worldwide. The pandemic has sparked extensive efforts to develop therapeutic strategies targeting either the virus itself or human proteins involved in the infection, resulting in hundreds of potential drugs and numerous clinical trials. In the search for new anti-SARS-CoV-2 drug candidates, we focussed on natural products. Using the cyanobacteria as a source of new structures due to their unique metabolism, two spumigins were isolated from the Baltic cyanobacterium Nodularia spumigena and tested for their activity against SARS-CoV-2. These compounds efficiently reduced SARS-CoV-2 infection in human A549ACE2/TMPRSS2 cells and fully differentiated primary human airway epithelium cell systems, in which viral entry depends on activation of the viral spike protein by the cellular serine protease, such as TMPRSS2. In contrast, the compounds did not inhibit viral replication in Vero cells, which lack TMPRSS2 but have high levels of cysteine protease cathepsin L, which may serve as an alternative for spike protein activation. Biochemical assays showed that spumigins inhibit TMPRSS2 with an EC50 ranging from 17 to 85 nM at which no toxicity is observed. Good parameters of identified inhibitors prove that cyanobacteria may serve as a rich source for new scaffolds reaching beyond the canonical chemical combinatorial space.