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. 2015 Jun 10;5:10916.
doi: 10.1038/srep10916.

Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors From a 334-Million Member Library

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Free PMC article

Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors From a 334-Million Member Library

Alexander Litovchick et al. Sci Rep. .
Free PMC article

Abstract

A chemical ligation method for construction of DNA-encoded small-molecule libraries has been developed. Taking advantage of the ability of the Klenow fragment of DNA polymerase to accept templates with triazole linkages in place of phosphodiesters, we have designed a strategy for chemically ligating oligonucleotide tags using cycloaddition chemistry. We have utilized this strategy in the construction and selection of a small molecule library, and successfully identified inhibitors of the enzyme soluble epoxide hydrolase.

Conflict of interest statement

All authors are current or former employees of X-Chem, Inc., a biotechnology company that operates DNA-encoded library technology as part of its business.

Figures

Figure 1
Figure 1. Study of polymerase read-through of single triazole junction.
A) Scheme for substrate synthesis and read-through study. B) LC trace of control read-through experiment using Klenow with wild-type template. UV detection at 495 nm. C) LC trace of read-through products using Superscript IIITM. D) LC trace of read-through using Klenow fragment. E) Mass spectrum of major peak in trace D).
Figure 2
Figure 2
A) Scheme of a chemical ligation–based library synthesis strategy; B) Structure of compound 11.
Figure 3
Figure 3. Study of Klenow read-through using FAM-labeled primer.
A) Scheme and LCMS data for read-through of double triazole template 9. UV detection at 495 nm. B) Scheme and LCMS data for read-through of triple triazole template 10.
Figure 4
Figure 4. Scheme for encoded library synthesis.
a) 2,259 5′-azido-3′-TIPS propargyl tags, Cu(OAc)2, sodium ascorbate, TBTA; b) 2,259 primary amines, NaBH3CN, 60 deg. C; c) TBAF; d) 666 5′-azido-3′-TIPS propargyl tags, Cu(OAc)2, sodium ascorbate, TBTA; e) 3 × 222 bromoaryl acids, DMT-MM f) 669 5′-azido-3′-TIPS propargyl tags, Cu(OAc)2, sodium ascorbate, TBTA; g) 667 boronic acids and esters, Pd(PPh3)4, CsCO3. Remaining 2 wells were encoded nulls, and received no reagent or palladium catalyst and no boronate, respectively.
Figure 5
Figure 5. Visualization of library population after selection against sEH.
The family indicated in blue was defined by two structurally related boronates. Compound 12 was designed as an exemplar of the indicated family.

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References

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