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Feb 26, 2015
 |  BC Innovations  |  Tools & Techniques

The Power of Two

Finding strong binders from dual-display barcoded chemical libraries

The goal of chemical libraries is to contain enough molecules that even targets with uncommon binding sites can find the rare compound that binds with high affinity. Rather than synthesizing hundreds of thousands of molecules, a Swiss group has played a different numbers game by designing a dual-display system that employs two sub-libraries of hundreds of molecules attached to the 5' or 3' ends of complementary DNA strands. The system can be used to select molecule pairs that bind two sites on a target with higher affinity together than either molecule alone, but it doesn't solve the problem of how to link the two binders to build a therapeutic agent.

"The idea of taking two 100-micromolar compounds and getting a 10-nanomolar compound by linking them together is tremendously exciting," said Derek Lowe, a medicinal chemist and author of a widely read blog on drug research.

But the advantage of the DNA pairing isn't only in bringing molecular fragments together to amplify their affinity. It's also in the fact that it grows the effective library size by multiplying rather than adding compound numbers.

"We generate a large combinatorial diversity because we can mix sub-libraries and obtain large numbers of combinations," said Dario Neri, principal investigator on the study and a professor of chemistry and applied biosciences at the Swiss Federal Institute of Technology Zurich (ETHZ).

He added: "If one sub-library contains 1,000 compounds on one DNA strand and the other sub-library contains another 1,000 compounds on the complementary strand of the same DNA, that creates one million combinations."

Neri is also a co-founder of Philogen S.p.A., a biotech that has developed screening systems for antibody-based therapeutics for angiogenesis.

To enable the compounds to be identified, each DNA strand was designed to contain a unique barcode for the molecule attached that could be decoded rapidly using next-generation sequencing (See Figure: Finding binding).

According to Neri, the double-stranded DNA therefore...

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