Brian Paegel, PhD

Associate Professor
Department of Chemistry
Florida Campus



Scripps Research Joint Appointments

Associate Professor, Department of Molecular Medicine
Faculty, Graduate Program

Research Focus

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.

 


Education

Ph.D. (Chemistry), University of California, Berkeley, 2003
B.S. (Chemistry), Duke University, 1998

Professional Experience

2017-2017 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

Awards & Professional Activities

NSF CAREER Award (2013)
NIH Director's New Innovator Award (2011)
NIH Pathway to Independence Award (2007)
NIH NRSA Postdoctoral Fellow (2004)

Selected References

All Publications

MacConnell, A. B., Price, A. K. & Paegel, B. M. An integrated microfluidic processor for DNA-encoded combinatorial library functional screening. (2017). ACS Combinatorial Science, 19(3), 181-192. 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. (2017). ACS Combinatorial Science, 19(1), 9-14. 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. (2017). ACS Chemical Biology, 12(1), 234-243. PMCID: PMC5250564.

Cochrane, W. G., Hackler, A. L., Cavett, V. J., Price, A. K. & Paegel, B. M. Integrated, continuous emulsion creamer. (2017). Analytical Chemistry, 89(24), 13227-13234.

MacConnell, A. B. & Paegel, B. M. Poisson statistics of combinatorial library sampling predict false discovery rates of screening. (2017). ACS Combinatorial Science, 19(8), 524-532. PMCID: PMC5558193.

Price, A. K. & Paegel, B. M. Discovery in droplets. (2016). Analytical Chemistry, 88, 339. PMCID: PMC4865373.

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. (2016). Proceedings of the National Academy of Sciences of the United States of America, 113(51), 14686-14691. PMCID: PMC5187733.

Malone, M. L. & Paegel, B. M. What is a "DNA-compatible" reaction?. (2016). ACS Combinatorial Science, 18(4), 182-187. PMCID: PMC4946796.

Price, A. K., MacConnell, A. B. & Paegel, B. M. hvSABR: photochemical dose-response bead screening in droplets. (2016). Analytical Chemistry, 88(5), 2904-2911. PMCID: PMC4776284.

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. (2015). ACS Combinatorial Science, 17(9), 518-534. PMCID: PMC4571006.


Links

Pubmed Publication List