Next-Generation DNA-Encoded Library Technologies for Smarter Drug Discovery

DNA-Encoded Library (DEL) technology is an increasingly popular method for hit discovery. Tagging individual compounds with unique DNA barcodes allows simultaneous testing of up to billions of different moieties against nearly any target (including difficult groups, e.g. protein-protein interactions) in a generalized binding assay. Hits are then identified by sequencing and decoding the DNA tags of the molecules which bind to the target protein. Altogether, a DEL discovery campaign at DyNAbind can be run at about ten times the speed and one-tenth the cost of a traditional high-throughput screening process.

Despite the promise of DEL technologies for accelerating early stage drug discovery, certain limitations with the first generation of the technology have held back the power of DEL programs. The commonly used synthetic strategies for large library production prevent meaningful quality control, and often cause a number of problems with library quality. Furthermore, multiple rounds of split-and-pool synthesis can result in ""molecular obesity"" and generate hits that are unacceptable as starting points for medicinal chemistry. Meanwhile the need for multiple rounds of next-generation DNA sequencing in experiment optimization presents a time bottleneck, while also presenting more opportunities for false positive hits via base reading errors in the DNA codes. Finally, months can be spent in hit validation, where each hit compound is resynthesized off-DNA for individual testing.

DyNAbind, along with the lab of Professor Yixin Zhang (TU Dresden), has developed technologies which diminish these problems to introduce a more reliable DEL process. Our Dynamic Chemical Libraries offer high-level quality control of the libraries and greatly boost signal-to-noise ratio while reducing false positive rates. The Path-Coding Algorithm takes advantage of the DNA information space to create codes which automatically detect and correct sequencing errors, further reducing false positives. Finally, the Binding Profiler system allows the use of on-DNA compounds for validation, reducing the time needed from up to months to just a few days. As a validation of these technologies, we present a full hit discovery campaign against Carbonic Anhydrase II. Hits are detected in a normal selection and affinity maturation approach and profiled through hit validation, before the most promising compound is then resynthesized and linked off-DNA for validation in a functional assay.

Authors

Francesco Reddavide(1)
Stephan Heiden(1)
Laura Krämer(2)
Weilin Yin(2)
Yixin Zhang(2)
Michael Thompson(1)

Organisations

DyNAbind GmbH(1)
Technische Universität Dresden(2)

Presenting author

Michael Thompson, CEO, DyNAbind GmbH
michael.thompson@dynabind.com
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