These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
2 files

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

submitted on 17.10.2020, 00:28 and posted on 19.10.2020, 10:35 by Michal Avital-Shmilovici, Xiaohe Liu, Thomas Shaler, Andrew Lowenthal, Pauline Bourbon, Janey Snider, Arlyn Tambo-ong, Claire Repellin, Kenya Yniguez, Lidia Sambucetti, Peter Madrid, Nathan Collins
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 method utilizes Fiber-optic Array Scanning Technology (FAST) to screen bead-based libraries of synthetic compounds at a rate of 5 million compounds per minute (~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 femtomole scale by chemical fragmentation and highresolution mass spectrometry. The versatility and throughput of the platform was 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 (ASGPR), IL-6, IL-6 receptor and TNFα. Hits with 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.


DARPA Fold F(X) program N66001-14-C-4059;


Email Address of Submitting Author


SRI International


United States

ORCID For Submitting Author


Declaration of Conflict of Interest