Precision Discovery of Novel Inhibitors of Human Cancer Target HsMetAP1 from Vast Unexplored Metagenomic Diversity

Microbial natural products are specialized metabolites that have long been a rich source of human therapeutics. While the chemical diversity encoded in the genomes of microbes is believed to be large, the productivity of this modality has waned as traditional fermentation-based discovery methods have been plagued by high-rates of rediscovery, inefficient scaling, and incompatibility with target-based drug discovery. Here, we demonstrate a scalable discovery platform that couples dramatically improved assembly of deep-sequenced metagenomic samples with highly efficient, target-focused, in silico search strategies and synthetic biology to discover multiple novel inhibitors of human methionine aminopeptidase-1 (HsMetAP1), a validated oncology target. For one of these novel inhibitors, metapeptin B, we demonstrate sub-micromolar potency, strong selectivity for HsMetAP1 over HsMetAP2 and leverage natural congeners to rapidly elucidate key SAR elements. Our 'next-gen' discovery platform overcomes many of the challenges constraining traditional methods, implies the existence of vast, untapped chemical diversity in nature, and demonstrates computationally-enabled precision discovery of modulators of human proteins of interest. ### Competing Interest Statement Multiple authors are/were employees of Zymergen, Inc.