Biomedical Engineering Reference
In-Depth Information
(a)
(b)
(c)
NH
2
a
b
c
d
5
′
3
′
“routing”
NH
2
a
b
c
d
3
′
(1) chemical reaction
(2) elute and mix
(3) repeat for all
codes/building blocks
a
b
c
d
5
′
3
′
FIGURE 11.6
Single-pharmacophore DNA-encoded chemical libraries. DNA-encoded
library formats: (a) library DNA conjugate: multiple sets of building blocks and corresponding
DNA-coding tags are assembled stepwise by split-pool combinatorial reactions; (b) library
DNA routed: DNA tags are used both for library encoding and for programming the library
assembly; (c) library DNA directed: multiple building blocks are assembled on the coding
DNA-oligonucleotide using DNA-directed reactions.
Numerous strategies have been explored for the assembly of single-pharmacophore
DNA-encoded libraries, featuring the implementation of various combinatorial chem-
istry techniques. Nonetheless, such libraries can be mainly grouped as follows: (a)
library DNA conjugate, essentially based on a stepwise combinatorial split-pool syn-
thesis and encoding (Figure 11.6a; see Section 11.2.2.1) [54-58]; (b) library DNA-
routed (Figure 11.6b, see Section 11.2.2.2) in which the DNA appendage is used both
for encoding and for programming the library assembly [59]; and (c) library DNA
directed, in which DNA-directed reactions are used for the synthesis and encoding
of the compounds displayed (Figure 11.6c, see Section 11.2.2.3) [60,61].
As shown in Figure 11.6, independent of the strategy pursued for library construc-
tion, the molecule displayed is generally assembled by the combinatorial incorpo-
ration of multiple sets of building blocks in iterative fashion. Therefore, the use of
highly efficient chemical reactions, which work well in a DNA-compatible solvent
such as water, and preserve the integrity of the DNA tags, is often crucial for the
synthesis of high-quality single-pharmacophore DNA-encoded chemical libraries.
11.2.2.1 DNA-Conjugate Libraries
Single-pharmacophore DNA-encoded chem-
ical libraries can be efficiently synthesized by straight DNA conjugation of building
blocks and reagents in combinatorial fashion. Philochem (a spin-off company at ETH
Zurich, Switzerland) and GlaxoSmithKline (former Praecis Pharmaceuticals) inde-
pendently invented and industrially developed various formats of DNA-conjugate
libraries for drug discovery purposes [54-56,58,62].
Philochem has pioneered the pool-split-pool approach to the construction of vari-
ous DNA-conjugate libraries [54,55,57]. The strategy, as depicted in Figure 11.7, fea-
tures five sequential steps: (i) linking of a first set of
n
chemical compounds (i.e.,
n
=
20) to distinct 5
-reactive oligonucleotides (i.e., synthetic 5
-amino-oligonucleotide);
