Functionality‐Independent DNA Encoding of Complex Natural Products

Ma, Peixiang; Xu, Hongtao; Li, Jie; Lu, Fengping; Ma, Fei; Wang, Shuyue; Xiong, Huan; Wang, Wei; Buratto, Damiano; Zonta, Francesco; Wang, Nan; Liu, Kaiwen; Hua, Tian; Liu, Zhi‐Jie; Yang, Guang; Lerner, Richard A.

doi:10.1002/ange.201901485

Cited by 22 publications

(13 citation statements)

References 58 publications

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“…Two general approaches, conventional split-pool synthesis in the presence of DNA and late-stage DNA annotation of existing NPs, [56,57] both require an orthogonal bifunctional chemical linker compatible with aqueous reaction condition and DNAs. Two general approaches, conventional split-pool synthesis in the presence of DNA and late-stage DNA annotation of existing NPs, [56,57] both require an orthogonal bifunctional chemical linker compatible with aqueous reaction condition and DNAs.…”

Section: Discussionmentioning

confidence: 99%

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Wang

et al. 2019

Advanced Science

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are encoded by unique DNA sequences as identification "barcodes," and are assembled combinatorial using split-andpool strategy or alternative procedures via DNA-compatible reactions. [7][8][9] DELs comprising millions or even billions of DNA-tagged druglike molecules can be effectively synthesized via this technology and screened against various protein targets of interest in a single pooled assay. In a typical affinity-based selection experiment, when non-and low-affinity binders are washed away, the DNA tag of the remaining compounds can be amplified using polymerase chain reaction and the relative frequency of the remaining compounds before and after selection is determined by counting the number of DNA tags in high-throughput DNA sequencing experiments. [10,11] To date, a large number of high-quality hits have been identified by the DEL technology for various therapeutically relevant targets, such as kinases, [12] phosphatases, [13] and G-protein coupled receptors. [14] Several drug candidates derived from their corresponding DEL hits, such as soluble epoxide hydrolase inhibitor GSK2256294, and death domain receptor-associated adaptor kinase RIP1 inhibitor GSK2982772 have progressed to latestage clinical development, [15,16] further emphasizing DEL as a powerful technology for small molecular drug discovery.Despite these successes, the great potential of DEL technology in drug discovery has not yet been fully realized. One of the most fundamental challenges is the synthesis of high-quality libraries with more structural diversity, which in turn depends on the development of new and robust DNA-compatible reactions that allow more flexibility in DEL's design and synthesis. Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. However, the environmental toxicity and high costs of aryl halides have hindered their large-scale applications in industry. Thus, much attention has been paid to phenol-derived electrophiles recently, [27] which, as compared to aryl halides, offer a more sustainable starting material because most of them are readily available from biomass. [28] In addition, phenol modules are also important components of natural products (NPs), bioactive molecules, and pharmaceutical drugs. Coupling reactions with Using (hetero)aryl fluorosulfonates as versatile electrophiles, facile on-DNA cross-coupling reactions of Suzuki, Sonogashira, and Buchwald are reported here. Notably, all of these reactions show excellent functional group tolerance, mild reaction conditions (relative low temperature and open to air), rich heterocyclic coupling partners, and more importantly, DNA-compatibility. Thus, these new reactions based on efficient formation of C(sp 2 )-C(sp 2 ), C(sp 2 )-C(sp), and C(s...

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Section: Discussionmentioning

confidence: 99%

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Wang

et al. 2019

Advanced Science

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“…Therefore, it may be prudent for future screening efforts to focus on different libraries. One potential untapped resource is the use of DNA-encoded libraries, which can provide numbers of compounds unobtainable through traditional and combinatorial chemistry routes and have been recently reviewed (151,152).…”

Section: Looking Forwardmentioning

confidence: 99%

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

O’Brien

Wilkinson

Roman

2019

Journal of Biological Chemistry

102

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Edited by Henrik G. Dohlman G protein-coupled receptors (GPCRs) play critical roles in regulating processes such as cellular homeostasis, responses to stimuli, and cell signaling. Accordingly, GPCRs have long served as extraordinarily successful drug targets. It is therefore not surprising that the discovery in the mid-1990s of a family of proteins that regulate processes downstream of GPCRs generated great excitement in the field. This finding enhanced the understanding of these critical signaling pathways and provided potentially new targets for pharmacological intervention. These regulators of G-protein signaling (RGS) proteins were viewed by many as nodes downstream of GPCRs that could be targeted with small molecules to tune signaling processes. In this review, we provide a brief overview of the discovery of RGS proteins and of the gradual and continuing discovery of their roles in disease states, focusing particularly on cancer and neurological disorders. We also discuss high-throughput screening efforts that have led to the discovery first of peptide-based and then of small-molecule inhibitors targeting a subset of the RGS proteins. We explore the unique mechanisms of RGS inhibition these chemical tools have revealed and highlight the most up-to-date studies using these tools in animal experiments. Finally, we discuss the future opportunities in the field, as there are clearly more avenues left to be explored and potentials to be realized.

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“…This progress has had a profound influence in the pharmaceutical industry by accelerating hit identification in drug discovery, sometimes for heretofore ''un-druggable'' targets. The popularity of DELs has also led to the development of new chemistries for DNA-compatible reactions, such as diversity-orientated synthesis (DOS) (Christopher et al, 2019), metal-or nonmetal-mediated diverse synthesis (Wang et al, 2019;Xiong et al, 2020;Xu et al, 2019Xu et al, , 2020 and late-stage DNA annotation (Ma et al, 2019), all in an effort to expand the chemical space coverage of DELs into more complex molecular structures. Currently, the diversity of DELs contains not only an unprecedented number of simple chemicals but also a collection of highly sophisticated stereo and spatial structures.…”

Section: Introductionmentioning

confidence: 99%

“…DEL may be the only method that allows for simultaneous selection of many members of a library on the basis of affinity alone. Late-stage DNA encoding of natural products has been shown to yield selectable libraries with small numbers that are nevertheless rich in structural diversity (Ma et al, 2019). Such encoding technology could be applied to other encoding molecules, such as peptide nucleic acids (PNAs) (Daguer et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Selection of Small Molecules that Bind to and Activate the Insulin Receptor from a DNA-Encoded Library of Natural Products

Xie

Wang

et al. 2020

iScience

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Although insulin is a life-saving medicine, administration by daily injection remains problematic. Our goal was to exploit the power of DNA-encoded libraries to identify molecules with insulin-like activity but with the potential to be developed as oral drugs. Our strategy involved using a 10 4 -member DNA-encoded library containing 160 Traditional Chinese Medicines (nDEL) to identify molecules that bind to and activate the insulin receptor. Importantly, we used the natural ligand, insulin, to liberate bound molecules. Using this selection method on our relatively small, but highly diverse, nDEL yielded a molecule capable of both binding to and activating the insulin receptor. Chemical analysis showed this molecule to be a polycyclic analog of the guanidine metformin, a known drug used to treat diabetes. By using our protocol with other, even larger, DELs we can expect to identify additional organic molecules capable of binding to and activating the insulin receptor.

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Functionality‐Independent DNA Encoding of Complex Natural Products

Cited by 22 publications

References 58 publications

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

Selection of Small Molecules that Bind to and Activate the Insulin Receptor from a DNA-Encoded Library of Natural Products

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