4.7 Article

Mega-High-Throughput Screening Platform for the Discovery of Biologically Relevant Sequence-Defined Non-Natural Polymers

Journal

ACS CENTRAL SCIENCE
Volume 8, Issue 1, Pages 86-101

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.1c01041

Keywords

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Funding

  1. DARPA Fold F (X) program [N66001-14-C-4059]

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Combinatorial methods allow for the synthesis of large chemical libraries, but screening and sequencing remain challenging. This study developed a novel technology for efficient screening and sequencing of billion-compound synthetic libraries. The versatility and high-throughput of the platform were demonstrated through screening two libraries and finding hits with low nanomolar binding affinities.
Combinatorial methods enable the synthesis of chemical libraries on scales of millions to billions of compounds, but the ability to efficiently screen and sequence such large libraries has remained a major bottleneck for molecular discovery. We developed a novel technology for screening and sequencing libraries of synthetic molecules of up to a billion compounds in size. This platform utilizes the fiber-optic array scanning technology (FAST) to screen bead-based libraries of synthetic compounds at a rate of 5 million compounds per minute (similar to 83 000 Hz). This ultra-high-throughput screening platform has been used to screen libraries of synthetic self-readable non-natural polymers that can be sequenced at the femtomole scale by chemical fragmentation and high-resolution mass spectrometry. The versatility and throughput of the platform were demonstrated by screening two libraries of non-natural polyamide polymers with sizes of 1.77M and 1B compounds against the protein targets K-Ras, asialoglycoprotein receptor 1 (ASGPR), IL-6, IL-6 receptor (IL-6R), and TNF alpha. Hits with low nanomolar binding affinities were found against all targets, including competitive inhibitors of K-Ras binding to Raf and functionally active uptake ligands for ASGPR facilitating intracellular delivery of a nonglycan ligand.

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