Biomedical Engineering Reference
In-Depth Information
FIGURE 11.5
Second generation of DNA encoded chemical libraries DNA-encoded library
formats displaying chemical compounds attached directly to the coding oligonucleotides.
(a) Single-pharmacophore format: a single oligonucleotide is covalently linked to a putative
binding molecule; (b) dual-pharmacophore format: multiple pairing oligonucleotides each
displaying a covalently linked chemical compound.
haloaromatic tagging, and electronic encoding are a few of the numerous encoding
strategies explored in that decade [52,53]. The lack of signal amplification upon
binding to the target at extremely low concentrations (typically in the subnanomolar
range) was an insurmountable limit for detection of the library members after the
selection process. The stunning amplifiability properties of the DNA appeared to be
the exceptional tool.
Therefore, at the beginning of the new millennium, DNA-encoded chemical library
technology experienced a revival. The technology was pursued through exploration of
completely new avenues. The bead as structural linkers between the chemical moiety
and the coding oligonucleotide (see Figure 11.4) was omitted through attaching
the candidate-binding molecule directly to the DNA-coding fragment. Today, this
second generation of DNA encoded chemical libraries can be conveniently classified
as 'single- and dual-pharmacophore libraries, depending on whether a single or
multiple oligonucleotides display a covalently linked molecule (Figure 11.5).
11.2.2 Single-Pharmacophore DNA-Encoded Chemical Libraries
The covalent linkage of a unique chemical entity to a single extremity of an oligonu-
cleotide tag represents the simplest format of a DNA-encoded chemical library. The
major advantage of single-pharmacophore libraries is that following selection against
a target antigen of choice, the selected binding compounds can be used straightfor-
wardly as hits for further drug discovery developments (e.g., medicinal chemistry
optimization), resynthesizing the compound without the oligonucleotide appendage.
