Bioassay‐guided Isolation of SARS‐CoV‐2 Viral Entry Inhibitors From the Brown Algae <i>Lobophora variegata</i> Identifies Fucoxanthin as a Selective ACE‐2/Spike Inhibitor

The continual emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, as well as unwanted side effects, limited worldwide availability, and risk of drug resistance from approved antivirals, continue to limit the effectiveness of coronavirus disease 2019 treatment. To continue to uncover natural products (NPs) that can inhibit validated biochemical targets of coronaviruses, we focused on a subset of brown algae extracts from Puerto Rico that demonstrated potential anti-SARS-CoV-2 activity through selective disruption of the viral Spike-receptor binding domain (RBD) to the host angiotensin-converting enzyme-2 (ACE2) cellular entry receptor, which in turn led to further evaluation of a Lobophora variegata organic extract. Employing bioassay-guided fractionation and modern NPs dereplication tools, we quickly identified fucoxanthin as an active constituent with selective inhibitory activity against spike-RBD/ACE-2 binding while also exhibiting moderate potency in vitro toward pseudo-virus-infected VERO cells. Preliminary in silico docking demonstrated that fucoxanthin binds stably at the RBD-spike protein interface and has provided a hypothesized binding site for further chemical and biological studies.