Discovery and Biosynthetic Interrogation of a Cobalt-Containing Terpene-Polyketide-Nonribosomal Peptide Tribrid with Anticoronavirus Activity

The structural complexity of natural products arises from the complexity of their biosynthetic pathways and directly contributes to their biological activities. Guided by this principle, we screened 500 microbial extracts using high-throughput screening to identify structurally novel inhibitors of coronavirus main protease, 3CL^pro. We discovered and structurally characterized a new scaffold, cobaltribin, the only isolated cobalt-containing natural product except vitamin B12 cobalamins. We further analyzed cobaltribin analogs to expand this unique class of anticoronavirus compounds. Furthermore, evidence from our bioinformatic, isotope labeling, and gene deletion analyses suggested that cobaltribin is a tribrid natural product resulting from an unprecedented terpene-polyketide (PK)-nonribosomal peptide (NRP) trihybridized biosynthesis. Notably, cobaltribin inhibits live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in infected Vero E6 cells without toxicity to the host, demonstrating its promise as a therapeutic candidate against SARS-CoV-2.