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

TLDR

Drug development often relies on high‑throughput cell‑based screening of large compound libraries, but the lack of miniaturized, parallel chemistry and incompatibility between synthesis and screening makes the process expensive and inefficient. This study demonstrates an on‑chip platform that integrates solution‑based synthesis of compound libraries with high‑throughput biological screening (chemBIOS). The chemBIOS platform accommodates both organic solvents for synthesis and aqueous solutions for screening, enabling 75 parallel three‑component reactions to produce a lipidoid library, which is then characterized by MALDI‑MS, formed into lipoplexes on‑chip, and screened in cells. The complete workflow—from library synthesis to cell screening—requires only 3 days and about 1 mL of total solutions, illustrating chemBIOS’s potential to boost efficiency and accelerate drug development.

Abstract

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.