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.

Asymmetry of Dual-Display DNA-Encoded Chemical Libraries

“…Since the synthetic and purification steps are partitioned for the two complementary DNA strands, dual-display DELs tend to have superior purity compared to single-pharmacophore libraries of the same number of diversity elements. Practically, dual-display DELs permit the discovery of synergistic pairs of ligands, in a fashion comparable to fragment based drug discovery (FBDD). , However, it is necessary to engineer linkers between the binding moieties after selection experiments, as it is the case with FBDD approaches. − While new methodologies have been developed to transition from double-stranded to single-stranded DELs, rendering the libraries more modular and versatile for synthesis and selections, − dual-display DELs enable innovative strategies for affinity-based selections such as affinity maturation of known hits and (photo)­cross-linking to biological targets in solution or on cell surfaces . Thanks to its continued optimization, the field of dual-display DELs now offers a panel of options for starting drug discovery projects. ,− …”

Reversible and Fully Controllable Generation of Organo-Soluble DNA (osDNA)

“…A DEL is a mixture of large numbers (millions to billions) of drug-like molecules of small molecular weight, where each molecule is conjugated to a specific and unique DNA-barcode that encodes its chemical structure. − A typical DEL molecule is a hybrid drug-like molecule harboring a DNA label attached with a chemical linker and that was generated by the serial addition of BBs onto a scaffold, using a combinatorial approach (e.g., split-and-pool protocol). The combinatorial approach gives rise to libraries containing millions to billions of compounds, − and importantly, it requires that the chemical reactions happen in the presence of DNA, and therefore in aqueous solution. Due to this important limitation, the DNA-compatible chemical space is fairly limited.…”

Ionic Liquids: Momentous Tools in Transdermal Delivery of Biomacromolecules

“…In recent decades, numerous bioactive macromolecular drug candidates, including peptides, [1] antibodies, [2,3] and nucleic acids, [4] have been developed owing to the emergence of combinatorial chemistry and high throughput screening. [5] Biomacromolecules are essential for treating many diseases, especially those that are difficult to cure, such as cancers [6][7][8][9][10] and autoimmune diseases. [11] The Food and Drug Administration DOI: 10.1002/adtp.202200332 authorized 16 new medications in the first half of 2022, [12] approximately 40% of which were biologics.…”