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| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| DNA-encoded chemical library | 2/6 | https://en.wikipedia.org/wiki/DNA-encoded_chemical_library | reference | science, encyclopedia | 2026-05-05T10:04:16.238098+00:00 | kb-cron |
The concept of DNA-encoding was first described in a theoretical paper by Sydney Brenner and Richard Lerner in 1992 in which was proposed to link each molecule of a chemically synthesized entity to a particular oligonucleotide sequence constructed in parallel and to use this encoding genetic tag to identify and enrich active compounds. In 1993 the first practical implementation of this approach was presented by J Nielsen, S. Brenner and K. Janda and similarly by the group of M.A. Gallop. Brenner and Janda suggested to generate individual encoded library members by an alternating parallel combinatorial synthesis of the heteropolymeric chemical compound and the appropriate oligonucleotide sequence on the same bead in a “split-&-pool”-based fashion (see below). Since unprotected DNA is restricted to a narrow window of conventional reaction conditions, until the end of the 1990s a number of alternative encoding strategies were envisaged (i.e. MS-based compound tagging, peptide encoding, haloaromatic tagging, encoding by secondary amines, semiconductor devices.), mainly to avoid inconvenient solid phase DNA synthesis and to create easily screenable combinatorial libraries in high-throughput fashion. However, the selective amplificability of DNA greatly facilitates library screening and it becomes indispensable for the encoding of organic compounds libraries of this unprecedented size. Consequently, at the beginning of the 2000s DNA-combinatorial chemistry experienced a revival. The beginning of the millennium saw the introduction of several independent developments in DEL technology. These technologies can be classified under two general categories: non-evolution-based and evolution-based DEL technologies capable of molecular evolution. The first category benefits from the ability to use off the shelf reagents and therefore enables rather straightforward library generation. Hits can be identified by DNA sequencing, however DNA translation and therefore molecular evolution is not feasible by these methods. The split and pool approaches developed by researchers at Praecis Pharmaceuticals (now owned by GlaxoSmithKline), Nuevolution (Copenhagen, Denmark) and encoded self- assembled chemical (ESAC) technology developed in the laboratory of Prof D. Neri (Institute of Pharmaceutical Science, Zurich, Switzerland) fall under this category. ESAC technology sets itself apart being a combinatorial self-assembling approach which resembles fragment based hit discovery (Fig 1b). Here DNA annealing enables discrete building block combinations to be sampled, but no chemical reaction takes place between them. Examples of evolution-based DEL technologies are DNA-routing developed by Prof. D.R. Halpin and Prof. P.B. Harbury (Stanford University, Stanford, CA), DNA-templated synthesis developed by Prof. D. Liu (Harvard University, Cambridge, MA) and commercialized by Ensemble Therapeutics (Cambridge, MA) and YoctoReactor technology. developed and commercialized by Vipergen (Copenhagen, Denmark). These technologies are described in further detail below. DNA-templated synthesis and YoctoReactor technology require the prior conjugation of chemical building blocks (BB) to a DNA oligonucleotide tag before library assembly, therefore more upfront work is required before library assembly. Furthermore, the DNA tagged BBs enable the generation of a genetic code for synthesized compounds and artificial translation of the genetic code is possible: That is the BB's can be recalled by the PCR-amplified genetic code, and the library compounds can be regenerated. This, in turn, enables the principle of Darwinian natural selection and evolution to be applied to small molecule selection in direct analogy to biological display systems; through rounds of selection, amplification and translation.
== Non-evolution based technologies ==
== Combinatorial libraries == Combinatorial libraries are special multi-component compound mixtures that are synthesized in a single stepwise process. They differ from collection of individual compounds as well as from a series of compounds prepared by parallel synthesis. Combinatorial libraries have important features. ″ Mixtures are used in their synthesis. The use of mixtures ensures the very high efficiency of the process. Both reactants could be mixtures but for practical reasons the split-mix procedure is used: one mixture is divided into portions that are coupled with the BBs. The mixtures are so important that there is no combinatorial library without using a mixture in the synthesis, and if a mixture is used in a process inevitably combinatorial library forms. ″ Components of the libraries need to be present in nearly equal molar quantities. In order to achieve this as closely as possible the mixtures are divided into equal portions and after pooling a thorough mixing is needed. ″ Since the structure of components is unknown deconvolution methods need to be used in screening. For this reason, encoding methods had been developed. Coding molecules are attached to the beads of the solid support that record the coupled BBs and their sequence. One of these methods is encoding by DNA oligomers. ″ It is a remarkable feature of combinatorial libraries that the whole compound mixture can be screened in a single process. Since both the synthesis and screening are very efficient procedures the use of combinatorial libraries in pharmaceutical research leads to enormous savings. In solid phase combinatorial synthesis only a single compound forms in each bead. For this reason, the number of components in the library can't exceed the number of beads of the solid support. This means that the number of components in such libraries is limited. This restraint was eliminated by Harbury and Halpin. In their synthesis of DELs, the solid support is omitted and BBs are attached directly to the encoding DNA oligomers. This new approach helps to increase practically unlimitedly the number of components of DNA encoded combinatorial libraries (DECLs).