20 research outputs found
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Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups.
In vivo compatible reactions have a broad range of possible applications in chemical biology and the pharmaceutical sciences. Here we report tetrazines that can be removed by exposure to isonitriles under very mild conditions. Tetrazylmethyl derivatives are easily accessible protecting groups for amines and phenols. The isonitrile-induced removal is rapid and near-quantitative. Intriguingly, the deprotection is especially effective with (trimethylsilyl)methyl isocyanide, and serum albumin can catalyze the elimination under physiological conditions. NMR and computational studies revealed that an imine-tautomerization step is often rate limiting, and the unexpected cleavage of the Si-C bond accelerates this step in the case with (trimethylsilyl)methyl isocyanide. Tetrazylmethyl-removal is compatible with use on biomacromolecules, in cellular environments, and in living organisms as demonstrated by cytotoxicity experiments and fluorophore-release studies on proteins and in zebrafish embryos. By combining tetrazylmethyl derivatives with previously reported tetrazine-responsive 3-isocyanopropyl groups, it was possible to liberate two fluorophores in vertebrates from a single bioorthogonal reaction. This chemistry will open new opportunities towards applications involving multiplexed release schemes and is a valuable asset to the growing toolbox of bioorthogonal dissociative reactions
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DNA-encoded chemical libraries: Advancing beyond conventional small-molecule libraries
DNA-encoded chemical libraries (DECLs) represent a promising tool in drug discovery. DECL technology allows the synthesis and screening of chemical libraries of unprecedented size at moderate costs. In analogy to phage-display technology, where large antibody libraries are displayed on the surface of filamentous phage and are genetically encoded in the phage genome, DECLs feature the display of individual small organic chemical moieties on DNA fragments serving as amplifiable identification barcodes. The DNA-tag facilitates the synthesis and allows the simultaneous screening of very large sets of compounds (up to billions of molecules), because the hit compounds can easily be identified and quantified by PCR-amplification of the DNA-barcode followed by high-throughput DNA sequencing. Several approaches have been used to generate DECLs, differing both in the methods used for library encoding and for the combinatorial assembly of chemical moieties. For example, DECLs can be used for fragment-based drug discovery, displaying a single molecule on DNA or two chemical moieties at the extremities of complementary DNA strands.
DECLs can vary substantially in the chemical structures and the library size. While ultralarge libraries containing billions of compounds have been reported containing four or more sets of building blocks, also smaller libraries have been shown to be efficient for ligand discovery. In general, it has been found that the overall library size is a poor predictor for library performance and that the number and diversity of the building blocks are rather important indicators. Smaller libraries consisting of two to three sets of building blocks better fulfill the criteria of drug-likeness and often have higher quality. In this Account, we present advances in the DECL field from proof-of-principle studies to practical applications for drug discovery, both in industry and in academia.
DECL technology can yield specific binders to a variety of target proteins and is likely to become a standard tool for pharmaceutical hit discovery, lead expansion, and Chemical Biology research. The introduction of new methodologies for library encoding and for compound synthesis in the presence of DNA is an exciting research field and will crucially contribute to the performance and the propagation of the technology.ISSN:0001-4842ISSN:1520-489
Chemical Space of DNA-Encoded Libraries
In
recent years, DNA-encoded chemical libraries (DECLs) have attracted
considerable attention as a potential discovery tool in drug development.
Screening encoded libraries may offer advantages over conventional
hit discovery approaches and has the potential to complement such
methods in pharmaceutical research. As a result of the increased application
of encoded libraries in drug discovery, a growing number of hit compounds
are emerging in scientific literature. In this review we evaluate
reported encoded library-derived structures and identify general trends
of these compounds in relation to library design parameters. We in
particular emphasize the combinatorial nature of these libraries.
Generally, the reported molecules demonstrate the ability of this
technology to afford hits suitable for further lead development, and
on the basis of them, we derive guidelines for DECL design
Stability of Oligonucleotide–Small Molecule Conjugates to DNA-Deprotection Conditions
Oligonucleotide conjugates of small
molecules are widely used in
chemical biology and have found increasing interest in the context
of DNA-encoded chemical libraries for drug discovery. Attachment of
molecules to DNA bound to the solid support is an attractive small-molecule
conjugation method that permits the use of organic solvents, rigorous
reaction conditions, and simple workup. However, the conjugated structures
must be resistant to the harsh DNA deprotection/cleavage conditions
and the stabilities of building blocks under various deprotection
conditions are mostly unexplored. In the present study, we analyzed
the stability of 131 structurally diverse fragments that contain amides
and amide-like elements during DNA deprotection protocols. Structural
features susceptible to decomposition in DNA deprotection conditions
were identified and a protocol that enabled the synthesis of DNA conjugates
with labile fragments on solid support was identified
Correction to “Large-Scale Detection of Metals with a Small Set of Fluorescent DNA-Like Chemosensors”
Combining pharmacophore models derived from DNA-encoded chemical libraries with structure-based exploration to predict Tankyrase 1 inhibitors
DNA-encoded chemical libraries (DECLs) interrogate the interactions of a target of interest with vast numbers of molecules. DECLs hence provide abundant information about the chemical ligand space for therapeutic targets, and there is considerable interest in methods for exploiting DECL screening data to predict novel ligands. Here we introduce one such approach and demonstrate its feasibility using the cancer-related poly-(ADP-ribose)transferase tankyrase 1 (TNKS1) as a model target. First, DECL affinity selections resulted in structurally diverse TNKS1 inhibitors with high potency including compound 2 with an IC50 value of 0.8 nM. Additionally, TNKS1 hits from four DECLs were translated into pharmacophore models, which were exploited in combination with docking-based screening to identify TNKS1 ligand candidates in databases of commercially available compounds. This computational strategy afforded TNKS1 inhibitors that are outside the chemical space covered by the DECLs and yielded the drug-like lead compound 12 with an IC50 value of 22 nM. The study further provided insights in the reliability of screening data and the effect of library design on hit compounds. In particular, the study revealed that while in general DECL screening data are in good agreement with off-DNA ligand binding, unpredictable interactions of the DNA-attachment linker with the target protein contribute to the noise in the affinity selection data
Large-Scale Detection of Metals with a Small Set of Fluorescent DNA-Like Chemosensors
An
important advantage of pattern-based chemosensor sets is their
potential to detect and differentiate a large number of analytes with
only few sensors. Here we test this principle at a conceptual limit
by analyzing a large set of metal ion analytes covering essentially
the entire periodic table, employing fluorescent DNA-like chemosensors
on solid support. A tetrameric “oligodeoxyfluoroside”
(ODF) library of 6561 members containing metal-binding monomers was
screened for strong responders to 57 metal ions in solution. Our results
show that a set of 9 chemosensors could successfully discriminate
the 57 species, including alkali, alkaline earth, post-transition,
transition, and lanthanide metals. As few as 6 ODF chemosensors could
detect and differentiate 50 metals at 100 ÎĽM; sensitivity for
some metals was achieved at midnanomolar ranges. A blind test with
50 metals further confirmed the discriminating power of the ODFs
Bioorthogonal Removal of 3‑Isocyanopropyl Groups Enables the Controlled Release of Fluorophores and Drugs in Vivo
Dissociative bioorthogonal
reactions allow for chemically controlling
the release of bioactive agents and reporter probes. Here we describe
3-isocyanopropyl substituents as masking groups that can be effectively
removed in biological systems. 3-Isocyanopropyl derivatives react
with tetrazines to afford 3-oxopropyl groups that eliminate diverse
functionalities. The study shows that the reaction is rapid and can
liberate phenols and amines near-quantitatively under physiological
conditions. The reaction is compatible with living organisms as demonstrated
by the release of a resorufin fluorophore and a mexiletine drug in
zebrafish embryos implanted with tetrazine-modified beads. The combined
benefits of synthetic ease, rapid kinetics, diversity of leaving groups,
high release yields, and structural compactness, make 3-isocyanopropyl
derivatives attractive chemical caging moieties for uses in chemical
biology and drug delivery
Recommended from our members
Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups.
In vivo compatible reactions have a broad range of possible applications in chemical biology and the pharmaceutical sciences. Here we report tetrazines that can be removed by exposure to isonitriles under very mild conditions. Tetrazylmethyl derivatives are easily accessible protecting groups for amines and phenols. The isonitrile-induced removal is rapid and near-quantitative. Intriguingly, the deprotection is especially effective with (trimethylsilyl)methyl isocyanide, and serum albumin can catalyze the elimination under physiological conditions. NMR and computational studies revealed that an imine-tautomerization step is often rate limiting, and the unexpected cleavage of the Si-C bond accelerates this step in the case with (trimethylsilyl)methyl isocyanide. Tetrazylmethyl-removal is compatible with use on biomacromolecules, in cellular environments, and in living organisms as demonstrated by cytotoxicity experiments and fluorophore-release studies on proteins and in zebrafish embryos. By combining tetrazylmethyl derivatives with previously reported tetrazine-responsive 3-isocyanopropyl groups, it was possible to liberate two fluorophores in vertebrates from a single bioorthogonal reaction. This chemistry will open new opportunities towards applications involving multiplexed release schemes and is a valuable asset to the growing toolbox of bioorthogonal dissociative reactions