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Combinatorial technology revitalized by DNA-encoding.

ABSTRACT: Combinatorial chemistry invented nearly 40 years ago was welcomed with enthusiasm in the drug research community. The method offered access to a practically unlimited number of new compounds. The new compounds however are mixtures, and methods had to be developed for the identification of the bioactive components. This was one of the reasons why the method could not providethe expected cornucopia of new drugs. Among the different screening methods, two approaches seem to offer the best results. One of them is based on the intrinsic property of the combinatorial split and pool solid-phase synthesis: One compound forms on each bead of the solid support. Different methods have been developed to encode the beads and identify the structure of compounds formed on them. The most important method applies DNA oligomers for encoding. As a second approach in screening, DNA-encoded combinatorial libraries are synthesized omitting the solid support and the mixtures are screened in solution using affinity binding methods. Libraries containing billions and even trillions of components are synthesized and successfully tested, which led to the identification of a significant number of new leads.

SUBMITTER: Furka A

PROVIDER: S-EPMC8554669 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Data storage in DNA has recently emerged as a promising archival solution, offering space-efficient and long-lasting digital storage solutions. Recent studies suggest leveraging the inherent redundancy of synthesis and sequencing technologies by using composite DNA alphabets. A major challenge of this approach involves the noisy inference process, obstructing large composite alphabets. This paper introduces a novel approach for DNA-based data storage, offering, in some implementations, a 6.5-fold increase in logical density over standard DNA-based storage systems, with near-zero reconstruction error. Combinatorial DNA encoding uses a set of clearly distinguishable DNA shortmers to construct large combinatorial alphabets, where each letter consists of a subset of shortmers. We formally define various combinatorial encoding schemes and investigate their theoretical properties. These include information density and reconstruction probabilities, as well as required synthesis and sequencing multiplicities. We then propose an end-to-end design for a combinatorial DNA-based data storage system, including encoding schemes, two-dimensional (2D) error correction codes, and reconstruction algorithms, under different error regimes. We performed simulations and show, for example, that the use of 2D Reed-Solomon error correction has significantly improved reconstruction rates. We validated our approach by constructing two combinatorial sequences using Gibson assembly, imitating a 4-cycle combinatorial synthesis process. We confirmed the successful reconstruction, and established the robustness of our approach for different error types. Subsampling experiments supported the important role of sampling rate and its effect on the overall performance. Our work demonstrates the potential of combinatorial shortmer encoding for DNA-based data storage and describes some theoretical research questions and technical challenges. Combining combinatorial principles with error-correcting strategies, and investing in the development of DNA synthesis technologies that efficiently support combinatorial synthesis, can pave the way to efficient, error-resilient DNA-based storage solutions.

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Combinatorial technology revitalized by DNA-encoding.

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