These are the leads you're looking for: LIGHTSABR could slash discovery costs

By Melissa Fassbender contact

- Last updated on GMT

The new technology has the ability to democratize high-throughput screening. (Imgae: iStock)
The new technology has the ability to democratize high-throughput screening. (Imgae: iStock)

Related tags: Drug discovery

Screening compound libraries is an important method for discovering new drugs, but has required a large, expensive facility – until now.

Scientists at The Scripps Research Institute (TSRI) have created a new screening system component​ that could make the platforms “orders of magnitude​” smaller and cheaper.

Most drug discovery occurs in robotic screening centers that use expensive and difficult-to-maintain compound libraries​,” said Brian M. Paegel, an associate professor at TSRI and the study’s principal investigator.

Often, the robotics involved​ can cost millions of dollars to establish and the compound libraries​ limited to a fixed collection of around 500,000 entities.

Our technology has the ability to democratize high-throughput screening, much as technology miniaturization has now moved genome sequencing into the hands of the many​,” expalined Paegel. “In principle, this type of technology can recapitulate many of the functions of a typical high-throughput screening center​.”

The new approach uses microfluidic droplets and integrated microfluidic circuitry to automate screening. According to Paegel, bead-based compound libraries are prepared by "split-and-pool​" combinatorial chemistry, which is capable of synthesizing million-compound libraries “on the fly for several hundred dollars​.”

The device, named LIGHTSABR (Light-Induced and Graduated High-Throughput Screening After Bead Release), was developed using a variety of recent engineering advances in microfabrication and droplet microfluidics.

According to Paegel, the most difficult part of the process was accurately delivering defined UV illumination intensity to a specific region of the circuit. “This involved implementing careful calibration experiments and the incorporation of sunscreen to block stray UV light​,” he explained.

How does it work?

A microfluidic circuit loads beads into microscopic water droplets in oil. Then, the beads are loaded with a compound attached to the bead surface using a photosensitive linker.

When the bead-containing droplets travel through a UV illumination region, the light cleaves the compound from the bead, allowing it to diffuse around the droplet​,” explained Paegel.

The droplet contains a biochemical experiment that measures the enzyme activity associated with HIV-1 replication.

If the compound inhibits the enzyme's function, the enzyme does not process indicator molecules and the droplet is distinguishable from others in which the enzyme's function remains uninhibited​,” added Paegel. “This difference in signal allows us to identify and isolate beads displaying potentially anti-viral compounds​.”

Moving forward

The researchers plan on implementing DNA-encoded miniaturized compound bead libraries in the integrated microfluidic LIGHTSABR device to identify inhibitors of HIV-1 protease – “a front-line target of several FDA-approved highly active anti-retroviral therapies​,” said Paegel.

They will initially work with other Scripps investigators, but are also pursuing options to spin out a start-up company to commercialize the technology.

Related topics: Preclinical Research, Preclinical

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