A mating mechanism to generate diversity for the Darwinian selection of DNA-encoded synthetic molecules

Recent advances in DNA-encoded dynamic libraries

“…[108][109][110][111][112][113] PNA-small-molecule (especially glycans) conjugates have been used to tailor the valency, distance, and geometry of the ligands in the assembly. 112,155,156 In principle, many of the PNA-encoded systems could be adapted to be dynamic and lead to novel applications; 39 however, so far, the examples are scarce. In 2017, the Winssinger group introduced dynamic hybridization in a multivalent assembly of PNA-glycan conjugates, which achieved an exceptional affinity gain and inhibitory activity against bacteria lectins, as compared with the monovalent ligands (Fig.…”

Converting Double-Stranded DNA-Encoded Libraries (DELs) to Single-Stranded Libraries for More Versatile Selections

“…Although having been used in early studies, 2 , 35 DELs encoded with single-stranded DNAs (ssDELs) are less abundant and they are often prepared with special encoding methods, such as DNA-templated synthesis (DTS), 36 DNA routing, 37 and DNA-directed assembly. 38 , 39 ssDNAs can also be used to assemble the encoded self-assembling chemical (ESAC) libraries 40 − 42 and DNA-encoded dynamic libraries. 43 − 51 Moreover, ssDELs are amendable to a number of selection methods suitable for nonimmobilized proteins, such as the interaction determination using unpurified proteins (IDUP), 52 , 53 the cross-linking-based methods, 54 − 60 and the selections against membrane proteins on/inside live cells ( Figure 1 c).…”

“…In fact, today, the majority of DELs are encoded with dsDNA tags. Although having been used in early studies, , DELs encoded with single-stranded DNAs (ssDELs) are less abundant and they are often prepared with special encoding methods, such as DNA-templated synthesis (DTS), DNA routing, and DNA-directed assembly. , ssDNAs can also be used to assemble the encoded self-assembling chemical (ESAC) libraries − and DNA-encoded dynamic libraries. − Moreover, ssDELs are amendable to a number of selection methods suitable for nonimmobilized proteins, such as the interaction determination using unpurified proteins (IDUP), , the cross-linking-based methods, − and the selections against membrane proteins on/inside live cells (Figure c). , In these methods, the ssDNA tag provides a site for hybridization with an additional DNA to covalently connect with the target upon binding. These methods may expand the target scope of DELs to more complex targets in a more biologically relevant environment. , In addition, a recent report showed that ssDELs had higher enrichment folds than dsDELs, especially for low- to moderate-affinity binders .…”

Aryl diazonium intermediates enable mild DNA-compatible C–C bond formation for medicinally relevant combinatorial library synthesis

“…Attracted by the DEL's cost and time efficiency, both academia and pharmaceutical companies have advanced DEL in terms of synthetic methodology and selection strategy. [18][19][20][21][22][23][24][25][26][27][28][29][30][31] Currently, although very few drug candidates in late-stage clinical trials stemmed from DEL, such as the soluble epoxide hydrolase (sEH) inhibitor GSK2256294 and the receptor-interacting protein (RIP1) kinase inhibitor GSK2982772, [32][33][34][35] DELs have shown their potential in high-throughput discovery of preliminary bioactive hits for dened targets, which might lead to the development of bioactive compounds or probes with structural optimization.…”