The idea of encoding a library of chemical compounds into fragments of DNA was first published in 1992 [1] and its first application was reported a year later in 1993 [2]. The idea consists of linking a molecule, a chemical entity, to a fragment of DNA, a biological one. By doing this, the DNA fragment functions as a bar code for the unique identification of the molecule. It’s like when you do your grocery shop, you buy your favourite brand of biscuits, then you go to the till, the shop assistant scans the barcode and your fav brand of biscuit pops up on the screen.
Since firstly introduced to the scientific community, DNA-encoded libraries have played a significant role in the field of drug discovery. If fact, they facilitate the process of identification and screening of libraries of chemical compounds with biological activity [3]. A biologically active compound is usually a molecule that can bind a protein, enzymes, or antibodies, and alter their activity. These are attractive molecules form a pharmaceutical point of view because they have the potential of becoming drug candidates.
This is how the lead identification works: a huge number of chemical compounds is generated by high-throughput screening (HTS) [4] for example. We call this great deal of compounds a library of compounds. This library is then screened against biological relevant targets (enzymes, receptors, antibodies etc) and scientists will look at some potential leads, i.e., molecules that binds the target. If they find any lead, they must be able to retrieve the chemical structure of this molecule and they do it by looking for the DNA fragment linked to it, or by finding its barcode essentially.
As the number of libraries to screen continues to increase, there’s a need to add diversity to the variety of DNA fragments to use as barcode. To address this problem, the Molander group at the University of Pennsylvania reported a number of light mediated techniques to create novel DNA-encoded libraries. In their first report, they described the use of Ni photo-redox dual catalysis to add alkylated fragments to DNA [5]. This procedure is quite simple and was conducted in an Eppendorf tube. All elements of the reaction, such as the fragment of DNA, the alkylated fragment, the nickel catalyst, photocatalysts, various additives and the solvent were added to the Eppendorf tube, exposed to blue light, shaken for as little as 10 min and the reaction was done. The alkylated fragment of DNA was obtained. Notably, this was an open air reaction which was quite unusual for these chemical transformations as they tend to occur under oxygen-free reaction conditions.
In another report [6], the author reported the photo-redox addition of carbon-based radicals to trifluoromethyl terminal alkene. It’s a complex concept from a chemical perspective which uses a redox active ester as photocatalyst. This ester initiated the formation of a carbon-based radical starting from a suitable carboxylic acid derivative. The radical was consequently added to the fragment of DNA to produce a chemically diverse library of DNA fragments. The schematic of this reaction is presented below (Figure 1).
The protocol showed in Figure 1 worked similarly as the one described for the Ni dual catalysis. Specifically, all components, photocatalysts, DNA fragment etc., were added to the Eppendorf tube, which was shaken, exposed to light for 10 min and the reaction produced the desired DNA derivative. Interestingly, this is a metal-free reaction and nickel isn’t needed which can potentially make isolation and purification of DNA fragments easy.
In their latest publication, Molander and co-workers re-employed this technique for the diversification of DNA fragments using a different light mediated transformation, the [2+2] photoaddition [7]. The [2+2] photoaddition is a well-known technique for the formation of spiro-heptanes but it was never reported for the incorporation of this chemical motif into DNA fragments. The authors used a protocol similar to those described above and, notably, a photocatalyst and visible light triggered this transformation. In fact, [2+2] photo-additions are usually UV-mediated reactions and don’t occur under visible light conditions. The authors applied the [2+2] photoaddition for the modification of great variety of DNA fragments, and this new publication adds to the range of methods and chemical entities that can be added to DNA fragments to create a diverse range of DNA-encoded libraries.
I made a small research and found two companies that sell DNA encoded libraries or outsource the process of finding leads. They are BOC Science with offices in UK and USA or MedChem Express based in USA and distributes worldwide. There’s a market for DNA-encoded libraries and I am glad to see how academic publications and research in general tag and address real problems such as simplifying the drug discovery process.
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References:
[1] Proc. Natl. Acad. Sci. U. S. A., 1992, 89, 5381–5384
[2] J. Am. Chem. Soc., 1993, 115, 9812–9815
[3] RSC Adv., 2021,11, 2359–2376
[4] High Throughput Screening — ScienceDirect
[5] J. Am. Chem. Soc. 2019, 141, 8, 3723–3732
[6] Chem. Sci., 2021,12, 12036–12045
[7] Chem. Sci., 2023, 14, 2713
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