Marrying chemistry with biology by combining on-chip solution-based combinatorial synthesis and cellular screening

Maximilian Benz,Alisa Rosenfeld,Mijanur R Molla,Alexander Böser,Pavel A Levkin

doi:10.1038/s41467-019-10685-0

Maximilian Benz, Alisa Rosenfeld + Show 3 more

Open Access

https://doi.org/10.1038/s41467-019-10685-0

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Abstract

Drug development often relies on high-throughput cell-based screening of large compound libraries. However, the lack of miniaturized and parallelized methodologies in chemistry as well as strict separation and incompatibility of the synthesis of bioactive compounds from their biological screenings makes this process expensive and inefficient. Here, we demonstrate an on-chip platform that combines solution-based synthesis of compound libraries with high-throughput biological screenings (chemBIOS). The chemBIOS platform is compatible with both organic solvents required for the synthesis and aqueous solutions necessary for biological screenings. We use the chemBIOS platform to perform 75 parallel, three-component reactions to synthesize a library of lipidoids, followed by characterization via MALDI-MS, on-chip formation of lipoplexes, and on-chip cell screening. The entire process from the library synthesis to cell screening takes only 3 days and about 1 mL of total solutions, demonstrating the potential of the chemBIOS technology to increase efficiency and accelerate screenings and drug development.

Highlights

The process of developing drugs as well as various other fundamental and applied biological experiments begins from the organic synthesis of compound libraries, followed by their highthroughput screening in biological assays to identify few active molecules (Fig. 1)
A compound library was synthesized using omniphilicomniphobic microarrays prepared on glass slides compatible with low surface tension organic liquids, called Low Surface Tension Liquids (LSTL) slides[19]
To manufacture LSTL slides, we first modified the surface of the glass slide with chlorovinylsilane to produce a monolayer of reactive vinyl groups on the surface

Summary

Introduction

The process of developing drugs as well as various other fundamental and applied biological experiments begins from the organic synthesis of compound libraries, followed by their highthroughput screening in biological assays to identify few active molecules (hits) (Fig. 1). Most of the compounds available in primary and secondary libraries are synthesized individually via standard organic synthesis usually involving large quantities of reagents and organic solvents This makes library synthesis an extremely lengthy and costly process taking many years and consuming valuable resources. Microarrays of DNA, peptide microarrays, small molecule microarrays or oligosaccharide microarrays produced by SPS have been demonstrated[7–13] These SPS methods have accelerated the development and investigation of large and diverse compound libraries because of their inherent miniaturization and parallelization, solutionbased synthesis offers a much broader scope of chemical reactions. If one chemist had to do this library synthesis at a speed of five compounds per day, it would take 55 years This illustrates the underlying problem for the entire field of drug discovery and explains the slow development and exorbitant costs (on average $2–4 billion per drug15–18) in this field essential to everyone. It remains very challenging to unify chemical synthesis with the biological screening part to enable faster transfer and utilization of the synthesized compounds in biological screenings, we believe this is the most efficient pathway to solve the aforementioned problems

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