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Paegel, Brian
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Paegel, Brian

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Positions

  • 2017 - Associate Professor Tenure, Chemistry , Scripps Research
  • 2017 - Associate Professor Tenure (Joint Appointment), Molecular Medicine , Scripps Research
  • 2009 - Faculty Member, Skaggs Graduate School of Chemical and Biological Sciences , Scripps Research
  • 2017 Associate Professor (Joint Appointment), Molecular Medicine , Scripps Research
  • 2015 - 2017 Associate Professor, Chemistry , Scripps Research
  • 2015 - 2017 Associate Professor, Molecular Therapeutics , Scripps Research
  • 2009 - 2015 Assistant Professor, Chemistry , Scripps Research
  • 2009 - 2015 Assistant Professor (Joint Appointment), Molecular Therapeutics , Scripps Research
  • 2004 - 2008 Postdoctoral Fellow with Dr. Gerald Joyce, Molecular Biology , Scripps Research

As the finish line of the Human Genome Project came into sight in 2003, the NIH founded the Molecular Libraries Program (MLP) to translate genomic data into therapeutics through a network of high-throughput screening (HTS) centers. These HTS centers, clones of industrial operations, house vast compound collections (~106 compounds) and robotic automation to screen the collections for biologically active molecules. A decade of discovery produced hundreds of probes — highly selective small molecules that modulate cellular function — but centralized HTS bears the same cost and infrastructure burdens of millennial DNA sequencing centers, fundamentally restricting access to the technology and constraining the rate of discovery. HTS today remains the exclusive province of pharmaceutical industry and a small handful of academic and government institutions.

My laboratory is building a next-generation platform to distribute and thereby democratize drug discovery. Miniaturization has played a central role in the development of this platform. We have miniaturized the compound collection by marrying DNA-encoded library (DEL) technology with solid-phase combinatorial synthesis. These DNA-encoded compound collections contain hundreds of millions of microscopic beads each displaying many copies of a small molecule library member and a corresponding DNA tag that encodes the library member's structure. To screen these microscopic library beads, we have engineered integrated microfluidic circuits that load individual DNA-encoded compound library beads into picoliter-scale droplets of assay reagent, photochemically cleave the compound from the bead into the droplet in a UV dose-dependent fashion (0.01–10 µM compound), incubate the dosed droplets, detect biological activity using laser-induced confocal fluorescence detection, and sort hit-containing droplets for PCR amplification and high-throughput sequencing. We are using this platform to screen for modulators of enzyme targets associated with various cancers, inflammation, and neurodegenerative diseases, and targets associated with viral and bacterial pathogens. At this stage, we can freely design and synthesize new DNA-encoded compound collections, develop assays for new targets, and screen the targets against our compound collections to generate lead molecules at a fraction of the time and cost scale of an HTS center.

Research Areas research areas

  • Cancer (UMLS)

Contact

  • briandna@scripps.edu

Websites

  • Brian Paegel, Ph.D.
  • Laboratory Website
  • Publications
  • Teaching
  • Background
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  • Identity
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Publications

recent publications
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  • Publications without PubMed PMIDs

  • academic article

    • Hu, Juan, Cochrane, Wesley G., Jones, Alexander X., Blackmond, D. G., Paegel, B. M. Chiral lipid bilayers are enantioselectively permeable Nature Chemistry  2021 13:786-791  DOI:10.1038/s41557-021-00708-z  PMID:34112989  PMCID:PMC8325640
    • Cochrane, W. G., Fitzgerald, P. R., Paegel, B. M. Antibacterial Discovery via Phenotypic DNA-Encoded Library Screening ACS Chemical Biology  2021 16:2752-2756  DOI:10.1021/acschembio.1c00714  PMID:34806373  PMCID:PMC8688339
    • Price, A. K., Paegel, B. M. Considerations for Achieving Maximized DNA Recovery in Solid-Phase DNA-Encoded Library Synthesis ACS Combinatorial Science  2020 22:649-655  DOI:10.1021/acscombsci.0c00101  PMID:32786319  PMCID:PMC7655546
    • Matos, J. L. M., Green, S. A., Chun, Y. G., Dang, V. Q., Dushin, R. G., Richardson, P., Chen, J. S., Piotrowski, D. W., Paegel, B. M., Shenvi, R. A. Cycloisomerization of Olefins in Water Angewandte Chemie-International Edition  2020  DOI:10.1002/anie.202003948  PMID:32285542
    • Hackler, A. L., FitzGerald, F. G., Dang, V. Q., Satz, A. L., Paegel, B. M. Off-DNA DNA-encoded library affinity screening ACS Combinatorial Science  2020 22:25-34  DOI:10.1021/acscombsci.9b00153  PMID:31829554  PMCID:PMC6957756
    • Ratnayake, A. S., Flanagan, M. E., Foley, T. L., Smith, J. D., Johnson, J. G., Bellenger, J., Montgomery, J. I., Paegel, B. M. A solution phase platform to characterize chemical reaction compatibility with DNA-encoded chemical library synthesis ACS Combinatorial Science  2019 21:650-655  DOI:10.1021/acscombsci.9b00113  PMID:31425646
    • Vallejo, D., Nikoomanzar, A., Paegel, B. M., Chaput, J. C. Fluorescence-activated droplet sorting for single-cell directed evolution ACS Synthetic Biology  2019 8:1430-1440  DOI:10.1021/acssynbio.9b00103  PMID:31120731
    • Cochrane, W. G., Malone, M. L., Dane, V. Q., Cavett, V., Satz, A. L., Paegel, B. M. Activity-Based DNA-Encoded Library Screening ACS Combinatorial Science  2019 21:425-435  DOI:10.1021/acscombsci.9b00037  PMID:30884226
    • Cochrane, W. G., Hackler, A. L., Cavett, V. J., Price, A. K., Paegel, B. M. Integrated, continuous emulsion creamer Analytical Chemistry  2017 89:13227-13234  DOI:10.1021/acs.analchem.7b03070  PMID:29124927
    • MacConnell, A. B., Paegel, B. M. Poisson statistics of combinatorial library sampling predict false discovery rates of screening ACS Combinatorial Science  2017 19:524-532  DOI:10.1021/acscombsci.7b00061  PMID:28682059  PMCID:PMC5558193
    • MacConnell, A. B., Price, A. K., Paegel, B. M. An integrated microfluidic processor for DNA-encoded combinatorial library functional screening ACS Combinatorial Science  2017 19:181-192  DOI:10.1021/acscombsci.6b00192  PMID:28199790  PMCID:PMC5350604
    • Malone, M. L., Cavett, V. J., Paegel, B. M. Chemoselective coupling preserves the substrate integrity of surface-immobilized oligonucleotides for emulsion PCR-based gene library construction ACS Combinatorial Science  2017 19:9-14  DOI:10.1021/acscombsci.6b00146  PMID:28064476  PMCID:PMC5243130
    • Mendes, K. R., Malone, M. L., Ndungu, J. M., Suponitsky-Kroyter, I., Cavett, V. J., McEnaney, P. J., MacConnell, A. B., Doran, T. M., Ronacher, K., Stanley, K., Utset, O., Walzl, G., et al. High-throughput identification of DNA-encoded IgG ligands that distinguish active and latent Mycobacterium tuberculosis infections ACS Chemical Biology  2017 12:234-243  DOI:10.1021/acschembio.6b00855  PMID:27957856  PMCID:PMC5250564
    • Tran, D. T., Cavett, V. J., Dang, V. Q., Torres, H. L., Paegel, B. M. Evolution of a mass spectrometry-grade protease with PTM-directed specificity Proceedings of the National Academy of Sciences of the United States of America  2016 113:14686-14691  DOI:10.1073/pnas.1609925113  PMID:27940920  PMCID:PMC5187733
    • Malone, M. L., Paegel, B. M. What is a "DNA-compatible" reaction? ACS Combinatorial Science  2016 18:182-187  DOI:10.1021/acscombsci.5b00198  PMID:26971959  PMCID:PMC4946796
    • Price, A. K., MacConnell, A. B., Paegel, B. M. hvSABR: photochemical dose-response bead screening in droplets Analytical Chemistry  2016 88:2904-2911  DOI:10.1021/acs.analchem.5b04811  PMID:26815064  PMCID:PMC4776284
    • Price, A. K., Paegel, B. M. Discovery in droplets Analytical Chemistry  2016 88:339  DOI:10.1021/acs.analchem.5b04139  PMID:26558892  PMCID:PMC4865373
    • MacConnell, A. B., McEnaney, P. J., Cavett, V. J., Paegel, B. M. DNA-encoded solid-phase synthesis: encoding language design and complex oligomer library synthesis ACS Combinatorial Science  2015 17:518-534  DOI:10.1021/acscombsci.5b00106  PMID:26290177  PMCID:PMC4571006
    • Price, A. K., MacConnell, A. B., Paegel, B. M. Microfluidic bead suspension hopper Analytical Chemistry  2014 86:5039-5044  DOI:10.1021/ac500693r  PMID:24761972  PMCID:PMC4029372
    • Matosevic, S., Paegel, B. M. Layer-by-layer cell membrane assembly Nature Chemistry  2013 5:958-963  DOI:10.1038/nchem.1765  PMID:24153375  PMCID:PMC4003896
    • Matosevic, S., Paegel, B. M. Stepwise synthesis of giant unilamellar vesicles on a microfluidic assembly line Journal of the American Chemical Society  2011 133:2798-2800  DOI:10.1021/ja109137s  PMID:21309555  PMCID:PMC3048828
    • Paegel, B. M. Microfluidic landscapes for evolution Current Opinion in Chemical Biology  2010 14:568-573  DOI:10.1016/j.cbpa.2010.07.023  PMID:20800535  PMCID:PMC2953605
    • Paegel, B. M., Joyce, G. F. Microfluidic compartmentalized directed evolution Chemistry & Biology  2010 17:717-724  DOI:10.1016/j.chembiol.2010.05.021  PMID:20659684  PMCID:PMC2912841
    • Paegel, B. M., Joyce, G. F. Darwinian evolution on a chip PLoS Biology  2008 6:e85  DOI:10.1371/journal.pbio.0060085  PMID:18399721  PMCID:PMC2288630
    • Paegel, B. M., Grover, W. H., Skelley, A. M., Mathies, R. A., Joyce, G. F. Microfluidic serial dilution circuit Analytical Chemistry  2006 78:7522-7527  DOI:10.1021/ac0608265  PMID:17073422  PMCID:PMC2566538
    • Doherty, E. A. S., Kan, C. W., Paegel, B. M., Yeung, S. H. I., Cao, S., Mathies, R. A., Barron, A. E. Sparsely cross-linked "nanogel" matrixes as fluid, mechanically stabilized polymer networks for high-throughput microchannel DNA sequencing Analytical Chemistry  2004 76:5249-5256  DOI:10.1021/ac049721x  PMID:15362880
    • Kamei, T., Paegel, B. M., Scherer, J. R., Skelley, A. M., Street, R. A., Mathies, R. A. Fusion of a-Si:H sensor technology with microfluidic bioanalytical devices Journal of Non-Crystalline Solids  2004 338:715-719  DOI:10.1016/j.jnoncrysol.2004.03.117
    • Kamei, T., Paegel, B. M., Scherer, J. R., Skelley, A. M., Street, R. A., Mathies, R. A. Integrated hydrogenated amorphous Si photodiode detector for microfluidic bioanalytical devices Analytical Chemistry  2003 75:5300-5305  DOI:10.1021/ac0301550  PMID:14710806
    • Paegel, B. M., Blazej, R. G., Mathies, R. A. Microfluidic devices for DNA sequencing: sample preparation and electrophoretic analysis Current Opinion in Biotechnology  2003 14:42-50  DOI:10.1016/s0958-1669(02)00004-6  PMID:12566001
    • Blazej, R. G., Paegel, B. M., Mathies, R. A. Polymorphism ratio sequencing: a new approach for single nucleotide polymorphism discovery and genotyping Genome Research  2003 13:287-293  DOI:10.1101/gr.396203  PMID:12566407  PMCID:PMC420372
    • Paegel, B. M., Yeung, S. H. I., Mathies, R. A. Microchip bioprocessor for integrated nanovolume sample purification and DNA sequencing Analytical Chemistry  2002 74:5092-5098  DOI:10.1021/ac0203645  PMID:12380835
    • Paegel, B. M., Emrich, C. A., Weyemayer, G. J., Scherer, J. R., Mathies, R. A. High throughput DNA sequencing with a microfabricated 96-lane capillary array electrophoresis bioprocessor Proceedings of the National Academy of Sciences of the United States of America  2002 99:574-579  DOI:10.1073/pnas.012608699  PMID:11792836  PMCID:PMC117347
    • Scherer, J. R., Paegel, B. M., Wedemayer, G. J., Emrich, C. A., Lo, J., Medintz, I. L., Mathies, R. A. High-pressure gel loader for capillary array electrophoresis microchannel plates Biotechniques  2001 31:1150-1154  PMID:11730021
    • Medintz, I. L., Paegel, B. M., Blazej, R. G., Emrich, C. A., Berti, L., Scherer, J. R., Mathies, R. A. High-performance genetic analysis using microfabricated capillary array electrophoresis microplates Electrophoresis  2001 22:3845-3856  DOI:10.1002/1522-2683(200110)22:18<3845::aid-elps3845>3.0.co;2-0  PMID:11700713
    • Medintz, I. L., Paegel, B. M., Mathies, R. A. Microfabricated capillary array electrophoresis DNA analysis systems Journal of Chromatography A  2001 924:265-270  DOI:10.1016/s0021-9673(01)00852-4  PMID:11521873
    • Paegel, B. M., Hutt, L. D., Simpson, P. C., Mathies, R. A. Turn geometry for minimizing band broadening in microfabricated capillary electrophoresis channels Analytical Chemistry  2000 72:3030-3037  DOI:10.1021/ac000054r  PMID:10939363
  • thesis

    • Microfabricated devices for integrated DNA sequencing 2003

featured in

  • Brian Paegel Wins Prestigious NSF Career Award  Newsletter
  • Scripps Florida Scientists Develop New Process to Create Artificial Cell Membranes  News Release
  • Scripps Research Appoints Three New Chemistry Faculty  Newsletter
  • Scripps Research Scientists Automate Molecular Evolution  News Release
  • Scripps Research Scientists Create Cell Assembly Line  News Release
  • Two Scripps Research Scientists Receive $1.5 Million NIH Innovator Awards  Newsletter
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Teaching

advisees

  • graduate advising relationship

    • Cochrane, Wesley Garret, Ph.D.  candidate, 2015 -
    • Fitzgerald, Patrick Ryan, Ph.D.  candidate, 2018 -
    • Hackler, Amber Lee, Ph.D.  candidate, 2016 -
    • Malone, Marie, Ph.D.  candidate, 2013 - 2018
    • MacConnell, Andrew, Ph.D.  candidate, 2012 - 2017
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Background

education and training

  • Ph.D. in Chemistry, University of California, Berkeley , with Dr. Richard Mathies 2003
  • B.S. in Chemistry, Duke University , magna cum laude 1998

awards and honors

  • NSF CAREER Award, 2013
  • Faculty Early Career Development (CAREER) Award, conferred by National Science Foundation, 2013
  • NIH Director's New Innovator Award, 2011
  • NIH Pathway to Independence Award, 2007
  • NIH Ruth L. Kirschstein National Research Service Award , 2005
  • NIH NRSA Postdoctoral Fellow, 2004
  • NIH Program in Genomics Fellow, 2000
  • ACS Division of Analytical Chemistry Fellow, 2000
  • Hypercube Scholar , 1998
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Contact

full name

  • Brian M. Paegel

geographic location

  • Scripps Florida 
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Identity

ORCID iD

  • ORCID iD http://orcid.org/0000-0002-6531-6693

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