Metabolomic Analysis and SARS-CoV-2 Antiviral Screening of Marine Cyanobacterial Library Identify Jobosnoic Acid, an Unreported Virus-selective Fatty Acid Inhibitor.

Current small molecule-based treatments for pre-exposure prophylaxis or active infection of SARS-CoV-2 remain poorly available worldwide and risk-inducing drug-induced viral resistance. Compounds that block multiple aspects of the SARS-CoV-2 replication cycle would be expected to pose a higher genetic barrier to drug resistance. Therefore, a marine algae extract library, and two distinct biochemical assays were used to screen for natural products that could inhibit two well-defined and validated COVID-19 drug targets, disruption of the Spike protein/ACE-2 interaction and the main protease (Mpro) of SARS-CoV-2. Upon initial screening of 86 crude extracts, we counter-screened and performed an untargeted metabolomic analysis of 16 cyanobacterial extracts. This orthogonal approach revealed three extracts with similar metabolomic and biological profiles, all from similar collection sites, leading to the isolation of an unusual saturated fatty acid, jobosnoic acid (1). We confirmed that 1 demonstrated dual inhibitory activity towards both viral targets while retaining activity against the Spike-RBD/ACE-2 interaction of the SARS-CoV-2 omicron variant. To initially explore its Structure Activity Relationship (SAR), we semi-synthetically accessed the methyl and benzyl ester derivatives of 1, both of which demonstrated acute loss of bioactivity in both SARS-CoV-2 biochemical assays. This effort has provided copious amounts of a fatty acid natural product that warrants further investigation in terms of SAR, determination of the absolute configuration of its C2 and C5 methyl substituents and understanding of its specific mechanisms of action and binding site to potentially describe new therapeutic avenues for SARS-CoV-2 drug development.