DNA-encoded chemical libraries (DEL) is a technology for the synthesis
and screening on unprecedented scale of collections of small molecule
compounds. DEL is used in medicinal chemistry to bridge the fields of
combinatorial chemistry and molecular biology. The aim of DEL
technology is to accelerate the drug discovery process and in
particular early phase discovery activities such as target validation
and hit identification.
DEL technology involves the conjugation of chemical compounds or
building blocks to short
DNA fragments that serve as identification
bar codes and in some cases also direct and control the chemical
synthesis. The technique enables the mass creation and interrogation
of libraries via affinity selection, typically on an immobilized
protein target. A homogeneous method for screening DNA-encoded
libraries has recently been developed which uses water-in-oil emulsion
technology to isolate, count and identify individual ligand-target
complexes in a single-tube approach. In contrast to conventional
screening procedures such as high-throughput screening, biochemical
assays are not required for binder identification, in principle
allowing the isolation of binders to a wide range of proteins
historically difficult to tackle with conventional screening
technologies. So, in addition to the general discovery of target
specific molecular compounds, the availability of binders to
pharmacologically important, but so-far “undruggable” target
proteins opens new possibilities to develop novel drugs for diseases
that could not be treated so far. In eliminating the requirement to
initially assess the activity of hits it is hoped and expected that
many of the high affinity binders identified will be shown to be
active in independent analysis of selected hits, therefore offering an
efficient method to identify high quality hits and pharmaceutical
1 DNA-encoded chemical libraries and display technologies
3 Non-evolution based technologies
3.2 Stepwise coupling of coding
DNA fragments to nascent organic
3.3 Combinatorial self-assembling
3.3.1 Encoded self-assembling chemical libraries
4 Evolution-based technologies
4.2 DNA-templated synthesis
5 3-Dimensional proximity-based technology (YoctoReactor technology)
5.1 Building a yR library
5.2 Homogeneous screening of yoctoreactor libraries
6 Decoding of DNA-encoded chemical libraries
6.1 Sanger sequencing-based decoding
6.2 Microarray-based decoding
6.3 Decoding by high throughput sequencing
7 See also
DNA-encoded chemical libraries and display technologies
Until recently, the application of molecular evolution in the
laboratory had been limited to display technologies involving
biological molecules, where small molecules lead discovery was
considered beyond this biological approach. DEL has opened the field
of display technology to include non-natural compounds such as small
molecules, extending the application of molecular evolution and
natural selection to the identification of small molecule compounds of
desired activity and function.
DNA encoded chemical libraries bear
resemblance to biological display technologies such as antibody phage
display technology, yeast display, m
RNA display and aptamer SELEX. In
antibody phage display, antibodies are physically linked to phage
particles that bear the gene coding for the attached antibody, which
is equivalent to a physical linkage of a “phenotype” (the protein)
and a “genotype” (the gene encoding for the protein ).
Phage-displayed antibodies can be isolated from large antibody
libraries by mimicking molecular evolution: through rounds of
selection (on an immobilized protein target), amplification and
translation. In DEL the linkage of a small molecule to an
DNA code allows the facile identification of binding
molecules. DEL libraries are subjected to affinity selection
procedures on an immobilized target protein of choice, after which
non-binders are removed by washing steps, and binders can subsequently
be amplified by polymerase chain reaction (PCR) and identified by
virtue of their
DNA code (e.g.by
DNA sequencing). In evolution-based
DEL technologies (see below) hits can be further enriched by
performing rounds of selection,
PCR amplification and translation in
analogy to biological display systems such as antibody phage display.
This makes it possible to work with much larger libraries.
Fig. 1 DNA-encoded library displaying chemical compounds Schematic
representation of DNA-encoded library displaying chemical compounds
directly attached to oligonucleotides. a) Library generated by
“stepwise combinatorial” assembling presenting a single
oligonucleotide covalently linked to a putative binding molecule. b)
Library construct in “combinatorial self-assembling” fashion
(Encoded Self-Assembling Chemical library). Multiple pairing
oligonucleotides display a covalently linked binding molecule
The concept of DNA-encoding was first described in a theoretical paper
by Brenner and 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 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).
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
DNA synthesis and to create easily screenable combinatorial
libraries in high-throughput fashion. However, the selective
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 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
Non-evolution based technologies
In order to apply combinatorial chemistry for the synthesis of
DNA-encoded chemical libraries, a Split-&-Pool approach was
pursued. Initially a set of unique DNA-oligonucleotides (n) each
containing a specific coding sequence is chemically conjugated to a
corresponding set of small organic molecules.Consequently, the
oligonucleotide-conjugate compounds are mixed ("Pool") and divided
("Split") into a number of groups (m). In appropriate conditions a
second set of building blocks (m) are coupled to the first one and a
further oligonucleotide which is coding for the second modification is
enzymatically introduced before mixing again. This
“split-&-pool” steps can be iterated a number of times (r)
increasing at each round the library size in a combinatorial manner
(i.e. (n x m)r).
Stepwise coupling of coding
DNA fragments to nascent organic
Fig. 3 DNA-encoded library by "Split-&-Pool stepwise coupling of
DNA fragments to nascent organic molecules An initial set of
multifunctional building blocks (FGn represents the different
orthogonal functional groups) are covalently conjugated to a
corresponding encoding oligonucleotide and reacted in a
split-&-pool fashion on a specific functional group (FG1 in red)
with a suitable collection of reagents. Following enzymatic encoding,
a further round of split-&-pool is initiated. At this stage the
second functional group (FG2 in blue) undergoes an additional reaction
step with a different set of suitable reagents. The identity of the
final modification could be ensured yet again by enzymatic DNA
encoding by means of a further oligonucleotide carrying a specific
A promising strategy for the construction of DNA-encoded libraries is
represented by the use of multifunctional building blocks covalently
conjugate to an oligonucleotide serving as a “core structure” for
library synthesis. In a ‘pool-and-split’ fashion a set of
multifunctional scaffolds undergo orthogonal reactions with series of
suitable reactive partners. Following each reaction step, the identity
of the modification is encoded by an enzymatic addition of
to the original
DNA “core structure”. The use of N-protected
amino acids covalently attached to a
DNA fragment allow, after a
suitable deprotection step, a further amide bond formation with a
series of carboxylic acids or a reductive amination with aldehydes.
Similarly, diene carboxylic acids used as scaffolds for library
construction at the 5’-end of amino modified oligonucleotide, could
be subjected to a
Diels-Alder reaction with a variety of maleimide
derivatives. After completion of the desired reaction step, the
identity of the chemical moiety added to the oligonucleotide is
established by the annealing of a partially complementary
oligonucleotide and by a subsequent
Klenow fill-in DNA-polymerization,
yielding a double stranded
DNA fragment. The synthetic and encoding
strategies described above enable the facile construction of
DNA-encoded libraries of a size up to 104 member compounds carrying
two sets of “building blocks”. However the stepwise addition of at
least three independent sets of chemical moieties to a tri-functional
core building block for the construction and encoding of a very large
DNA-encoded library (comprising up to 106 compounds) can also be
Encoded self-assembling chemical libraries
Fig. 4 ESAC library technology overview Small organic molecules are
coupled to 5’-amino modified oligonucleotides, containing a
hybridization domain and a unique coding sequence, which ensure the
identity of the coupled molecule. The ESAC library can be used in
single pharmacophore format (a), in affinity maturations of known
binders (b), or in de novo selections of binding molecules by self
assembling of sublibraries in DNA-double strand format (c) as well as
in DNA-triplexes (d). The ESAC library in the selected format is used
in a selection and read-out procedure (e). Following incubation of the
library (i) with the target protein of choice (ii) and washing of
unbound molecules (iii), the oligonucleotide codes of the binding
compounds are PCR-amplified and compared with the library without
selection on oligonucleotide micro-arrays (iv, v). Identified
binders/binding pairs are validated after conjugation (if appropriate)
to suitable scaffolds (vi).
Encoded Self-Assembling Chemical (ESAC) libraries rely on the
principle that two sublibraries of a size of x members (e.g. 103)
containing a constant complementary hybridization domain can yield a
combinatorial DNA-duplex library after hybridization with a complexity
of x2 uniformly represented library members (e.g. 106). Each
sub-library member would consist of an oligonucleotide containing a
variable, coding region flanked by a constant
DNA sequence, carrying a
suitable chemical modification at the oligonucleotide extremity.
The ESAC sublibraries can be used in at least four different
A sub-library can be paired with a complementary oligonucleotide and
used as a
DNA encoded library displaying a single covalently linked
compound for affinity-based selection experiments.
A sub-library can be paired with an oligonucleotide displaying a known
binder to the target, thus enabling affinity maturation strategies.
Two individual sublibraries can be assembled combinatorially and used
for the de novo identification of bindentate binding molecules.
Three different sublibraries can be assembled to form a combinatorial
Preferential binders isolated from an affinity-based selection can be
PCR-amplified and decoded on complementary oligonucleotide
microarrays or by concatenation of the codes, subcloning and
sequencing. The individual building blocks can eventually be
conjugated using suitable linkers to yield a drug-like high-affinity
compound. The characteristics of the linker (e.g. length, flexibility,
geometry, chemical nature and solubility) influence the binding
affinity and the chemical properties of the resulting binder.(Fig.3)
Bio-panning experiments on HSA of a 600-member ESAC library allowed
the isolation of the 4-(p-iodophenyl)butanoic moiety. The compound
represents the core structure of a series of portable albumin binding
molecules and of AlbufluorTM a recently developed fluorescein
angiographic contrast agent currently under clinical evaluation.
ESAC technology has been used for the isolation of potent inhibitors
of bovine trypsin and for the identification of novel inhibitors of
stromelysin-1 (MMP-3), a matrix metalloproteinase involved in both
physiological and pathological tissue remodeling processes, as well as
in disease processes, such as arthritis and metastasis.
In 2004, D.R. Halpin and P.B. Harbury presented a novel intriguing
method for the construction of DNA-encoded libraries. For the first
time the DNA-conjugated templates served for both encoding and
programming the infrastructure of the “split-&-pool” synthesis
of the library components. The design of Halpin and Harbury
enabled alternating rounds of selection,
PCR amplification and
diversification with small organic molecules, in complete analogy to
phage display technology. The DNA-routing machinery consists of a
series of connected columns bearing resin-bound anticodons, which
could sequence-specifically separate a population of DNA-templates
into spatially distinct locations by hybridization. According to
this split-and-pool protocol a peptide combinatorial library
DNA-encoded of 106 members was generated.
Nucleic acid templated chemistry
Fig. 2 DNA-encoded library by ‘DNA-templated synthesis’A library
of oligonucleotides (i.e. 64 different oligonucleotides) containing
three coding regions was hybridized to a library of reagent
compound-oligonucleotide conjugates (i.e. 4 reagent oligonucleotide
conjugates), able of pairing with the initial coding domain of the
template oligonucleotide. After transferring of the compounds on the
corresponding oligonucleotide template, the synthesis cycle was
repeated the desired number of times with further sets of carrier
compound-oligonucleotide conjugates (i.e. two rounds with four carrier
compound-oligonucleotide conjugates per round). Subsequently
functional selection was performed and the sequence of the binding
template amplified by PCR. Thus, DNA-sequencing allowed the
identification of the binding molecule.
In 2001 David Liu and co-workers showed that complementary DNA
oligonucleotides can be used to assist certain synthetic reactions,
which do not efficiently take place in solution at low
concentration. A DNA-heteroduplex was used to accelerate the
reaction between chemical moieties displayed at the extremities of the
DNA strands. Furthermore, the "proximity effect", which
accelerates bimolecular reaction, was shown to be distance-independent
(at least within a distance of 30 nucleotides). In a
sequence-programmed fashion oligonucleotides carrying one chemical
reactant group were hybridized to complementary oligonucleotide
derivatives carrying a different reactive chemical group. The
proximity conferred by the
DNA hybridization drastically increases the
effective molarity of the reaction reagents attached to the
oligonucleotides, enabling the desired reaction to occur even in an
aqueous environment at concentrations which are several orders of
magnitude lower than those needed for the corresponding conventional
organic reaction not DNA-templated. Using a DNA-templated set-up
and sequence-programmed synthesis Liu and co-workers generated a
DNA encoded library of macrocycles.
3-Dimensional proximity-based technology (YoctoReactor
The YoctoReactor (yR) is a 3D proximity-driven approach which exploits
the self-assembling nature of
DNA oligonucleotides into 3, 4 or 5-way
junctions to direct small molecule synthesis at the center of the
junction. Figure 5 illustrates the basic concept with a 4-way DNA
Fig. 5 Fundamental principle of the YoctoReactor. The center of 3, 4
and 5 way
DNA junctions (a 4-way junction is shown here) becomes a
yoctoliter-scale reactor where small molecule synthesis is facilitated
in what has been termed the YoctoReactor (yR). Colored circles depict
the chemical building blocks (BB) which are attached to carefully
DNA oligonucleotides (black lines). Upon
DNA annealing the BB
are brought into proximity at the center of the
DNA junction where
they undergo chemical reaction.
The center of the
DNA junction constitutes a volume on the order of a
yoctoliter, hence the name YoctoReactor. This volume contains a single
molecule reaction yielding reaction concentrations in the high mM
range. The effective concentration facilitated by the
accelerates chemical reactions that otherwise would not take place at
the actual concentration several orders of magnitude lower.
Building a yR library
Figure 6 illustrates the generation of a yR library using a 3-way DNA
Fig. 6 YoctoReactor library assembly. Stepwise assembly of a DEL
library using YoctoReactor technology. A 3-way reactor is shown here.
(a) Position 1 (P1) and P2 BB are brought into proximity and undergo a
chemical reaction in the presence of a helper oligonucleotide in P3.
(b) The structure is purified by polyacrylamide gel electrophoresis
(PAGE), the P1 and P2
DNA is ligated and the P2 linker is cleaved. (c)
P3 BB is annealed to the P1-P2 ligation product from step b, and a
chemical reaction between P2 and P3 BBs takes place. (d) The reaction
product is purified by PAGE, the
DNA is ligated and P3 linker is
cleaved yielding a compound (OOO) covalently attached to the folded
yR. (e) The yR is dismantled by primer extension yielding a
double-stranded display product exposing the reaction product for
selection and molecular evolution.
In summary, chemical building-blocks (BB) are attached via cleavable
or non-cleavable linkers to three types of bispecific DNA
oligonucleotides (oligo-BBs) representing each arm of the yR. To
facilitate synthesis in a combinatorial manner, the oligo-BBs are
designed such that the
DNA contains (a) the code for an attached BB at
the distal end of the oligo (colored lines) and (b) areas of constant
DNA sequence (black lines) to bring about the self-assembly of the DNA
into a 3-way junction (independently of the BB) and the subsequent
chemical reaction. Chemical reactions are performed via a stepwise
procedure and after each step the
DNA is ligated and the product
purified by polyacryamide gel electrophoresis. Cleavable linkers
(BB-DNA) are used for all but one position yielding a library of small
molecules with a single covalent link to the
DNA code. Table 1
outlines how libraries of different sizes can be generated using yR
Table 1. YoctoReactor library size. yR library size is a function of
the number of different functionalized oligos used in each position
and the number of positions in the
The yR design approach provides an unvarying reaction site with regard
to both (a) distance between reactants and (b) sequence environment
surrounding the reaction site. Furthermore, the intimate connection
between the code and the BB on the oligo-BB moieties which are mixed
combinatorially in a single pot confers a high fidelity to the
encoding of the library. The code of the synthesized products,
furthermore, is not preset, but rather is assembled combinatorially
and synthesized in synchronicity with the innate product.
Homogeneous screening of yoctoreactor libraries
A homogeneous method for screening yoctoreactor libraries (yR) has
recently been developed which uses water-in-oil emulsion technology to
isolate individual ligand-target complexes. Called Binder Trap
Enrichment (BTE), ligands to a protein target are identified by
trapping binding pairs (DNA-labelled protein target and yR ligand) in
emulsion droplets during dissociation dominated kinetics. Once
trapped, the target and ligand
DNA are joined by ligation, thus
preserving the binding information.
Hereafter, identification of hits is essentially a counting exercise:
information on binding events is deciphered by sequencing and counting
DNA - selective binders are counted with a much higher
frequency than random binders. This is possible because random
trapping of target and ligand is "diluted" by the high number of water
droplets in the emulsion. The low noise and background signal
characteristic of BTE is attributed to the "dilution" of the random
signal, the lack of surface artifacts and the high fidelity of the yR
library and screening method. Screening is performed in a single tube
method. Biologically active hits are identified in a single round of
BTE characterized by a low false positive rate.
BTE mimics the non-equilibrium nature of in vivo ligand-target
interactions and offers the unique possibility to screen for target
specific ligands based on ligand-target residence time because the
emulsion, which traps the binding complex, is formed during a dynamic
Decoding of DNA-encoded chemical libraries
Following selection from DNA-encoded chemical libraries, the decoding
strategy for the fast and efficient identification of the specific
binding compounds is crucial for the further development of the DEL
technology. So far, Sanger-sequencing-based decoding, microarray-based
methodology and high-throughput sequencing techniques represented the
main methodologies for the decoding of DNA-encoded library selections.
Sanger sequencing-based decoding
Although many authors implicitly envisaged a traditional Sanger
sequencing-based decoding, the number of codes to
sequence simply according to the complexity of the library is
definitely an unrealistic task for a traditional Sanger sequencing
approach. Nevertheless, the implementation of
Sanger sequencing for
decoding DNA-encoded chemical libraries in high-throughput fashion was
the first to be described. After selection and
of the DNA-tags of the library compounds, concatamers containing
multiple coding sequences were generated and ligated into a vector.
Sanger sequencing of a representative number of the
resulting colonies revealed the frequencies of the codes present in
the DNA-encoded library sample before and after selection.
DNA microarray is a device for high-throughput investigations widely
used in molecular biology and in medicine. It consists of an arrayed
series of microscopic spots (‘features’ or ‘locations’)
containing few picomoles of oligonucleotides carrying a specific DNA
sequence. This can be a short section of a gene or other
that are used as probes to hybridize a
RNA sample under
suitable conditions. Probe-target hybridization is usually detected
and quantified by fluorescence-based detection of fluorophore-labeled
targets to determine relative abundance of the target nucleic acid
Microarray has been used for the successfully decoding of
ESAC DNA-encoded libraries. The coding oligonucleotides
representing the individual chemical compounds in the library, are
spotted and chemically linked onto the microarray slides, using a
BioChip Arrayer robot. Subsequently, the oligonucleotide tags of the
binding compounds isolated from the selection are
PCR amplified using
a fluorescent primer and hybridized onto the DNA-microarray slide.
Afterwards, microarrays are analyzed using a laser scan and spot
intensities detected and quantified. The enrichment of the
preferential binding compounds is revealed comparing the spots
intensity of the DNA-microarray slide before and after selection.
Decoding by high throughput sequencing
According to the complexity of the
DNA encoded chemical library
(typically between 103 and 106 members), a conventional Sanger
sequencing based decoding is unlikely to be usable in practice, due
both to the high cost per base for the sequencing and to the tedious
procedure involved. High throughput sequencing technologies
exploited strategies that parallelize the sequencing process
displacing the use of capillary electrophoresis and producing
thousands or millions of sequences at once. In 2008 was described the
first implementation of a high-throughput sequencing technique
originally developed for genome sequencing (i.e. "454 technology") to
the fast and efficient decoding of a
DNA encoded chemical library
comprising 4000 compounds. This study led to the identification of
novel chemical compounds with submicromolar dissociation constants
towards streptavidin and definitely shown the feasibility to
construct, perform selections and decode DNA-encoded libraries
containing millions of chemical compounds.
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