Jeff Martell

Congratulations Pete, Zach, and team!

Congratulations @genlichem.bsky.social and Xiao! Very clever probe design.

Congratulations, Philip!

Bifunctional Catalysis of Aldol Reactions by Foldamer Dihydrazides: Assessment of Conformational Preorganization We previously reported that molecules containing two cyclic hydrazide units connected by a polymethylene linker could catalyze aldol condensations via a bifunctional mechanism. One hydrazide apparentl...

My work assessing the effect of preorganization on dihydrazide activity is out in @jacs.acspublications.org. We find that dihydrazides with flexible tethers can replicate much of the catalytic activity of complex dihydrazides with preorganized foldamer scaffolds. #Chemsky

doi.org/10.1021/jacs...

Congrats to Ashley Ogorek and @shubha-pani.bsky.social‬, who co-led this study, as well as the entire team: Eli, Jelena, Yichong, Fernando, Rachel, @xuhuihuangchem.bsky.social‬. This was a really fun collaboration with ‪@chembiobryan.bsky.social‬ - stay tuned for more to come!

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The enhanced bioorthogonality of the bCP ester enabled us to perform spatially-resolved RNA proximity labeling and RNA sequencing, including in human cells lines with high endogenous esterase activity.

9/n

The pCP / evolved BS2 pair performs well in multiple sub-compartments of mammalian cells.

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We teamed up with @xuhuihuangchem.bsky.social to perform structural modeling and substrate docking to gain insights into the beneficial mutations.

7/n

Using DEEPMACh, we evolved BS2 esterase to increase activity toward pCP esters more than 230-fold.

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To overcome this challenge, we developed a new platform, Directed Evolution of Enzymes via Masked Acid Chloride Probes ("DEEPMACh”). DEEPMACh combines yeast surface display with masked acylating probes, enabling rapid screening of >40 million enzyme mutants.

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…BS2 esterase shows very low activity toward the pCP ester.

4/n

The methylcyclopropyl (mCP) ester protecting group together with BS2 esterase has been applied as a bioorthogonal system, but background unmasking of mCP occurs in mammalian cells. We found that the bulkier phenylCP group was much more bioorthogonal! However…

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Context: combining bioorthogonal protecting groups with localized catalysts that unmask them is a powerful approach to modulate molecular activity. However, existing protecting groups are insufficiently bioorthogonal, or the catalysts that unmask them cannot be genetically targeted. 2/n

Directed Evolution of Enzymes for Bioorthogonal Chemistry Using Acid Chloride Proximity Labeling Combining bioorthogonal protecting groups with localized catalysts that can unmask them is a powerful approach to spatially and temporally modulate molecular activity. Enzymes are appealing catalysts ...

Excited to share a new pre-print on a joint study between my group and @chembiobryan.bsky.social‬! Directed Evolution of Enzymes for Bioorthogonal Chemistry Using Acid Chloride Proximity Labeling. chemrxiv.org/engage/chemr...
1/n

Thanks, Neel!

Thanks, Chang!

Thank you! We didn't run into mixing/order of addition issues. Nearly all components are already on DNA, and we add Cu last to commence the reaction. For mixing, we did vortexing then centrifugation, which worked well for our 20 uL scale reactions.

Really proud of Riley's preprint on a new class of chiral Lewis acid photocatalysts. This project benefitted from a terrific collab with @chemguyeli.bsky.social chemrxiv.org/engage/chemr...

Congratulations, Phill! Very well-deserved!

Thanks especially to Matt and Beck for collaborating with us to merge our platform with data science and ML, and to Josh and Daniel (‪@coonlab.bsky.social‬) for performing essential mass spec characterization of the DNA-small molecule conjugates.‬‬

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Big congrats to co-1st authors Caleb Cox and @edwardpimentel.bsky.social‬ who showed incredible persistence and creativity, and to all co-authors: Beck Miller, Daniel Nesbitt, Justice LeMonds, @ethan-hartman-125.bsky.social‬, Tate Hancock, Robert Kennedy, Josh Coon, and Matt Sigman.

11/n

Overall, we believe this platform opens fundamentally new opportunities in data-driven discovery, optimization, and mechanistic understanding of synergistic catalytic reactions. There are many new directions we’re excited to explore – stay tuned for more in the coming years!

10/n

Excitingly, we observed correlation between ML predicted DNA nanoscaffold yields and experimental DNA-free reactions, including for kinetic time courses and for reactants not represented in the original DNA nanoscaffold library.

9/n

We teamed up with Matt Sigman and Beck Miller to use data science in library design and to combine our datasets with ML to generate predictive models. The model covers 18,000 reactant combinations under many reaction conditions.

8/n

Using our platform, one researcher performed >500,000 reactions in parallel with less than 3 days of bench time. By incorporating standards and calibration curves, we obtained precise DNA-scaffolded reaction yields using DNA sequencing.

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Our approach draws inspiration from the pioneering work of David Liu on DNA-templated substrate coupling to screen for bond-forming reactions, www.nature.com/articles/nat... and the Vipergen Yoctoreactor which brings together 3 components for DNA-encoded small molecule synthesis.

6/n

Our platform works by 3 steps: 1) combinatorial self-assembly of a DNA nanoscaffold library, 2) Simultaneous scaffolded reactions and high-throughput selection of product-bearing nanoscaffolds 3) PCR amplification and next-generation DNA sequencing to identify successful reactions conditions.

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We wondered whether we could use DNA scaffolding and next-generation DNA sequencing to dramatically increase the throughput, allowing >500,000 reactions to be performed in parallel, with simultaneous reaction analysis by sequencing.

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Nanomole-scale high-throughput chemistry for the synthesis of complex molecules Automated technology enables chemical reaction optimization using micrograms of material.

Impressive advances in high-throughput experimentation (HTE) enable ~10^4 reactions to be performed in multi-well plates (www.science.org/doi/10.1126/...). However, this requires individual reaction setup and screening, increasing the analysis time proportionally.

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Synergistic catalysis can unlock new reactivity, but it presents a multidimensional screening challenge. In the example scenario below, there are >500,000 combinations.

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