PT  - JOURNAL ARTICLE
AU  - Oliver W. Liu
AU  - Scott Akers
AU  - Gabriella Alvarez
AU  - Stephanie Brown
AU  - Wenlong Cai
AU  - Zachary Charlop-Powers
AU  - Kevin Crispell
AU  - Tom H. Eyles
AU  - Sangita Ganesh
AU  - Ee-Been Goh
AU  - Peter M. Haverty
AU  - William W. Hwang
AU  - Matthew Jamison
AU  - John L. Kulp, Jr.
AU  - John L. Kulp III
AU  - Zachary Kurtz
AU  - Andrea Lubbe
AU  - Aleksandr Milshteyn
AU  - Parisa Mokthari
AU  - Stephen G. Naylor
AU  - Samuel Oteng-Pabi
AU  - Ross Overacker
AU  - Andrew W. Robertson
AU  - Helen van Aggelen
AU  - Usha Viswanathan
AU  - Xiao Yang
AU  - Sam Yoder
AU  - Steven L. Colletti
AU  - Devin R. Scannell
TI  - Precision Discovery of Novel Inhibitors of Cancer Target HsMetAP1 from Vast Metagenomic Diversity
AID  - 10.1101/2022.06.11.495772
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.11.495772
4099  - http://biorxiv.org/content/early/2022/08/30/2022.06.11.495772.short
4100  - http://biorxiv.org/content/early/2022/08/30/2022.06.11.495772.full
AB  - 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.Competing Interest StatementMultiple authors are/were employees of Zymergen, Inc.