Metal–oxide interfaces provide a new opportunity to improve catalytic activity based on electronic and chemical interactions at the interface. Constructing a high density of interfaces is essential in maximizing synergistic interactions. Here, we demonstrate that Cu–ceria interfaces made by sintering nanocrystals facilitate C–C coupling reactions in electrochemical reduction of CO2. The Cu/ceria catalyst enhances the selectivity of ethylene and ethanol production with the suppression of H2 evolution in comparison with Cu catalysts. The intrinsic activity for ethylene production is enhanced by decreasing the atomic ratio of Cu/Ce, revealing the Cu atoms near ceria are an active site for C–C coupling reactions. The ceria is proposed to weaken the hydrogen binding energy of adjacent Cu sites and stabilize an *OCCO intermediate via an additional chemical interaction with an oxygen atom of the *OCCO. This work offers new insights into the role of the metal–oxide interface in the electrochemical reduction of CO2 to high-value chemicals.

The design of small molecules that inhibit disease-relevant proteins represents a longstanding challenge of medicinal chemistry. Here, we describe an approach for encoding this challenge-the inhibition of a human drug target-into a microbial host and using it to guide the discovery and biosynthesis of targeted, biologically active natural products. This approach identi ed two previously unknown terpenoid inhibitors of protein tyrosine phosphatase 1B (PTP1B), an elusive therapeutic target for the treatment of diabetes and cancer. Both inhibitors target an allosteric site, which confers unusual selectivity, and can inhibit PTP1B in living cells. A screen of 24 uncharacterized terpene synthases from a pool of 4,464 genes uncovered additional hits, demonstrating a scalable discovery approach, and the incorporation of different PTPs into the microbial host yielded alternative PTP-speci c detection systems. Findings illustrate the potential for using microbes to discover and build natural products that exhibit precisely de ned biochemical activities yet possess unanticipated structures and/or binding sites.

The design of small molecules that inhibit disease-relevant proteins represents a longstanding challenge of medicinal chemistry. Here, we describe an approach for encoding this challenge—the inhibition of a human drug target—into a microbial host and using it to guide the discovery and biosynthesis of targeted, biologically active natural products. This approach identified two previously unknown terpenoid inhibitors of protein tyrosine phosphatase 1B (PTP1B), an elusive therapeutic target for the treatment of diabetes and cancer. Both inhibitors appear to target an allosteric site, which confers selectivity, and can inhibit PTP1B in living cells. A screen of 24 uncharacterized terpene synthases from a pool of 4,464 genes uncovered additional hits, demonstrating a scalable discovery approach, and the incorporation of different PTPs into the microbial host yielded alternative PTP-specific detection systems. Findings illustrate the potential for using microbes to discover and build natural products that exhibit precisely defined biochemical activities yet possess unanticipated structures and/or binding sites.

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