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Seminar Series: “The Revolution Will Be Compartmentalized” featuring Brian Paegel, Scripps Research Institute
October 23 @ 4:00 pm - 5:00 pm
Department Seminar Series:
The Revolution will be Compartmentalized: Chemical Synthesis and Analytical Technology for Distributed Drug Discovery
Professor Brian M. Paegel
The Scripps Research Institute, Jupiter, Florida
October 23, 2017
4:00 PM – 5:00 PM
Natural Sciences I, Room 1114
The NIH Molecular Libraries Program (MLP) was founded to translate the discoveries of the Human Genome Project into therapeutics through a network of high-throughput screening (HTS) centers. A decade of discovery produced hundreds of probes — highly selective small molecules that modulate cellular function — but centralized compound screening bears the same cost and infrastructure burdens of millennial DNA sequencing centers, which has limited access to the technology and, more significantly, the rate of small molecule discovery.
We are building a distributable drug discovery platform analogous to next-generation DNA sequencing. New DNA-encoded solid-phase synthesis strategies produce ultra-miniaturized compound libraries of microscopic bead each displaying many copies of a small molecule library member and a corresponding amplifiable DNA encoding its structure. Microfluidic instrumentation engineering for miniaturizing automated screening has now yielded integrated circuits that load individual 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 activity using laser-induced confocal fluorescence detection, and sort hit-containing droplets for PCR amplification and high-throughput sequencing. To demonstrate the feasibility of the platform, we synthesized a modest (~30k compounds) DNA-encoded combinatorial protease inhibitor library and developed droplet-scale biochemical assays of HIV-1 protease, ZIKV NS2B-NS3 protease, and cathepsin D.
Not only are the molecular libraries and screening technology deployable in any laboratory setting, but dose-response screening promises whole-library structure activity relationship profiles. The unprecedented molecular detail of these data will yield portfolios of new leads and replenish the pipeline of therapeutics, especially those targeting rapidly-evolving bacterial and viral pathogens.