Precision Discovery of Novel Inhibitors of Human Cancer Target HsMetAP1 from Vast Unexplored Metagenomic Diversity
Liu, O. W.; Akers, S.; Alvarez, G.; Brown, S.; Cai, W.; Charlop-Powers, Z.; Crispell, K.; Goh, E.-B.; Hwang, W. W.; Eyles, T. H.; Ganesh, S.; Haverty, P.; Kulp, J. L.; Kulp, J. L.; Kurtz, Z.; Lubbe, A.; Jamison, M.; Milshteyn, A.; Mokthari, P.; Naylor, S. G.; Oteng-Pabi, S.; Overacker, R.; Robertson, A. W.; van Aggelen, H.; Viswanathan, U.; Yang, X.; Yoder, S.; Colletti, S. L.; Scannell, D. R.
Show abstract
Microbial natural products have long been a rich source of human therapeutics. While the chemical diversity encoded in the genomes of microbes is large, this modality has waned as fermentation-based discovery methods have suffered from rediscovery, inefficient scaling, and incompatibility with target-based discovery paradigms. Here, we leverage a metagenomic partitioning strategy to sequence soil microbiomes at unprecedented depth and quality. We then couple these data with target-focused, in silico search strategies and synthetic biology to discover multiple novel natural product inhibitors of human methionine aminopeptidase-1 (HsMetAP1), a validated oncology target. For one of these, metapeptin B, we demonstrate sub-micromolar potency, strong selectivity for HsMetAP1 over HsMetAP2 and elucidate structure-activity relationships. Our approach overcomes challenges of traditional natural product methods, accesses vast, untapped chemical diversity in uncultured microbes, and demonstrates computationally-enabled precision mining of modulators of human proteins.
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