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Article
| Open Access
Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery
Targeted protein degradation (TPD) is an emerging therapeutic that can lead to proteasomal degradation of target proteins. Here, the authors combine nano-scale, automated synthesis and cell-based, direct-to-biology screening, allowing them to discover and profile Molecular Glues (MGs) degrading substrates via the Cereblon E3 ubiquitin ligase.
- Zefeng Wang
- , Shabnam Shaabani
- & Alexander Dömling
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Article
| Open Access
C5 methylation confers accessibility, stability and selectivity to picrotoxinin
Minor changes to complex structures can exert major influences on synthesis strategy and functional properties but synthetic difficulties can obstruct the exploration of natural product function. Here the authors explore two parallel series of picrotoxinin analogs and identify leads with selectivity between mammalian and insect ion channels.
- Guanghu Tong
- , Samantha Griffin
- & Ryan A. Shenvi
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Article
| Open Access
Catalytic 4-exo-dig carbocyclization for the construction of furan-fused cyclobutanones and synthetic applications
Aromatic ring fused cyclobutanone is a strained motif with broad applications. Here, the authors report a catalytic 4- exo-dig process, which proved successful to access furan-fused cyclobutanones that can serve as versatile synthetic blocks.
- Kemiao Hong
- , Yi Zhou
- & Xinfang Xu
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Article
| Open Access
Chemoenzymatic synthesis of genetically-encoded multivalent liquid N-glycan arrays
Cellular glycosylation is complex and heterogeneous, which is challenging to reproduce synthetically. Here, the authors report on enzymatic remodelling of multivalent glycosylated bacteriophages to produce genetically encoded library of N-glycans which can be used to measure glycan-protein interactions with lectins on the surface of live cells and organs.
- Chih-Lan Lin
- , Mirat Sojitra
- & Ratmir Derda
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Article
| Open Access
Diversity-oriented synthesis encoded by deoxyoligonucleotides
Most DNA-encoded library (DEL) syntheses are limited by the presence of sensitive DNA-based constructs. Here, the authors develop DOSEDO, a diverse 3.7 million compound DEL, generated through diversity-oriented synthesis that provides enhanced scaffold and exit vector diversity and gives validated binding hits for multiple protein targets.
- Liam Hudson
- , Jeremy W. Mason
- & Karin Briner
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Article
| Open Access
Isolation of full-length IgG antibodies from combinatorial libraries expressed in the cytoplasm of Escherichia coli
Discovery of full-length antibodies can be slow and labor intensive. Here, the authors describe a robust genetic assay for facile isolation of IgG antibodies from combinatorial libraries expressed in the cytoplasm of redox-engineered bacteria.
- Michael-Paul Robinson
- , Jinjoo Jung
- & Matthew P. DeLisa
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Article
| Open Access
High-affinity peptides developed against calprotectin and their application as synthetic ligands in diagnostic assays
A peptide was developed that binds to calprotectin, a marker of major inflammatory disorders, and found to be suited for diagnostic tests. The use of synthetic peptides in assays is of great interest due to their high precision, robustness and low price.
- Cristina Díaz-Perlas
- , Benjamin Ricken
- & Christian Heinis
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Article
| Open Access
Stereodefined polymetalloid alkenes synthesis via stereoselective boron-masking of polyborylated alkenes
Polyborylated-containing alkenes, hold promise as polymetalated building blocks for a wide variety of organic motifs, biologically-active compounds, and natural product synthesis, though strategies for their stereoselective synthesis are lacking. Here, the authors report concise, highly site-selective, and stereoselective boron-masking strategies for polyborylated alkenes.
- Nadim Eghbarieh
- , Nicole Hanania
- & Ahmad Masarwa
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Article
| Open Access
Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
Dual-pharmacophore DNA-Encoded Libraries (DELs) can generate large libraries, but linker optimisation is challenging. Here, the authors report a trio-pharmacophore DEL (T-DEL) for both de novo fragment identification and linker optimization of known fragment pairs.
- Meiying Cui
- , Dzung Nguyen
- & Yixin Zhang
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Article
| Open Access
Construction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein–protein interaction inhibitor
Chemical libraries with skeleton diversity are important for drug discovery. Here, the authors establish a synthetic methodology-based compound library (SMBL), and apply it to identify a small-molecule inhibitor to interrupt a challenging target: the protein–protein interaction (PPI) of GIT1/β-Pix.
- Jing Gu
- , Rui-Kun Peng
- & Qin Ouyang
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Article
| Open Access
Synthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale
Macrocycles have potential as therapeutics, but their libraries are currently not large enough for high-throughput screening. Here, the authors show a combinatorial approach to generate a library of almost 20’000 macrocycles by conjugating carboxylic-acid fragments to macrocyclic scaffolds, identifying nanomolar inhibitors against thrombin and binders of MDM2.
- Sevan Habeshian
- , Manuel Leonardo Merz
- & Christian Heinis
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Article
| Open Access
Droplet-based screening of phosphate transfer catalysis reveals how epistasis shapes MAP kinase interactions with substrates
Here, the authors use a droplet-based screen for phosphate transfer catalysis, testing variants of the human protein kinase MKK1 for its ability to activate its downstream target ERK2. Data reveal a flexible motif in the MKK1 docking domain that promotes efficient activation of ERK2, and suggest epistasis between the residues within that sequence.
- Remkes A. Scheele
- , Laurens H. Lindenburg
- & Florian Hollfelder
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| Open Access
MuSyC is a consensus framework that unifies multi-drug synergy metrics for combinatorial drug discovery
The lack of a unifying metric characterizing combinatorial drug interactions has impeded the development of combinatorial therapies. Here, the authors present MuSyC, a consensus synergy metric that overcomes several caveats associated with other, popular metrics.
- David J. Wooten
- , Christian T. Meyer
- & Carlos F. Lopez
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Article
| Open Access
Synergistic sequence contributions bias glycation outcomes
Advanced glycation end-products (AGEs), such as methylglyoxal-derived hydroimidazolone isomer (MGH-1), are associated with disease and age-related disorders, and occur spontaneously, so it is unclear why specific protein sites become modified with specific AGEs. Here, the authors use a combinatorial peptide library to determine the chemical features that favour MGH-1 formation for short peptides and demonstrate a key role of tyrosine in this process.
- Joseph M. McEwen
- , Sasha Fraser
- & Rebecca A. Scheck
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Article
| Open Access
Diversity-oriented functionalization of 2-pyridones and uracils
Diversity-oriented synthesis of 2-pyridone and uracil derivatives is in urgent need in medicinal chemistry as they are useful pharmacophores. Here the authors show that palladium/norbornene cooperative catalysis enabled dual-functionalization of iodinated 2- pyridones and uracils.
- Yong Shang
- , Chenggui Wu
- & Qianghui Zhou
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Article
| Open Access
Passerini-type reaction of boronic acids enables α-hydroxyketones synthesis
Multicomponent reactions enable the rapid construction of diverse molecular scaffolds with modularity and step economy. In this work, the authors report the use of boronic acids as carbon nucleophiles in a Passerini-type three-component coupling reaction towards an expanded inventory of α-hydroxyketones.
- Kai Yang
- , Feng Zhang
- & Qiuling Song
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Article
| Open Access
Biomimetic selenocystine based dynamic combinatorial chemistry for thiol-disulfide exchange
Thiol-disulfide exchange is an extensively used reversible reaction in dynamic combinatorial chemistry, but usually requires long time to reach equilibrium. Here, the authors employ selenocystine as a catalyst of thiol-disulfide exchange at low temperatures and basic pH, and show that it can promote disulfide bond formation during folding of a scrambled RNase A.
- Andrea Canal-Martín
- & Ruth Pérez-Fernández
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Article
| Open Access
Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases
Current histone microarrays cannot be used to directly study the transient interactions of histone deacetylases (HDACs). Here, the authors show that hydroxamic acid-modified microarrays can capture HDACs, provide insights into their substrate specificity, and serve to develop peptide inhibitors.
- Carlos Moreno-Yruela
- , Michael Bæk
- & Christian A. Olsen
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| Open Access
In vivo diversification of target genomic sites using processive base deaminase fusions blocked by dCas9
In vivo mutagenesis systems can often show restricted capabilities and deleterious off-site mutations. Here the authors fuse base deaminases to T7 RNA polymerase to mutate a target sequence and use dCas9 to define the boundaries of the diversified DNA.
- Beatriz Álvarez
- , Mario Mencía
- & Luis Ángel Fernández
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Article
| Open Access
Nature-inspired remodeling of (aza)indoles to meta-aminoaryl nicotinates for late-stage conjugation of vitamin B3 to (hetero)arylamines
Vitamin B3 derivatives display a range of biological activities. Here, the authors report the synthesis of meta-aminoaryl nicotinates, derivatives of vitamin B3, and their late-stage conjugation with (hetero)arylamines, ultimately expanding the chemical space for biomedical research.
- Begur Vasanthkumar Varun
- , Kannan Vaithegi
- & Seung Bum Park
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Article
| Open Access
A combined high-throughput and high-content platform for unified on-chip synthesis, characterization and biological screening
On-chip synthesis and screening has been used to automate drug discovery but on-chip analysis still remains a major limitation. Here, the authors report on a dendrimer-based surface patterning method to create nanodroplet arrays on materials which allow for on-chip high-throughput analysis.
- Maximilian Benz
- , Arndt Asperger
- & Pavel A. Levkin
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Article
| Open Access
Decarboxylative thiolation of redox-active esters to free thiols and further diversification
Thiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. Here, the authors report a visible light-mediated decarboxylative thiolation of alkyl redox-active esters to free thiols and the in situ product diversification of a number of thiol derivatives.
- Tianpeng Cao
- , Tianxiao Xu
- & Saihu Liao
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Article
| Open Access
Ring-opening functionalizations of unstrained cyclic amines enabled by difluorocarbene transfer
Cyclic amines are commonly present in natural products and synthetic compounds, but methods for their skeletal diversification are limited. Here, the authors report a strategy for selective ring-opening functionalization of unstrained cyclic amines to pluripotent products that can be further diversified.
- Youyoung Kim
- , Joon Heo
- & Sangwon Seo
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Article
| Open Access
Unsymmetrical polysulfidation via designed bilateral disulfurating reagents
The functionalization of a sulfur-sulfur motif is synthetically challenging but highly desired for the production of bioactive compounds. Here, the authors report a disulfurating reagent for sequential and modular assembly of polysulfides where the S-S motif is functionalized with different C-, N- and S-nucleophiles.
- Jiahui Xue
- & Xuefeng Jiang
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Article
| Open Access
Ultra-large chemical libraries for the discovery of high-affinity peptide binders
Synthetic peptide libraries can access broad chemical space, but generally examine only ~ 106 compounds. Here, the authors show that in-solution affinity selection, interfaced with nLC-MS/MS sequencing, can identify binders from fully randomized synthetic libraries of 108 members.
- Anthony J. Quartararo
- , Zachary P. Gates
- & Bradley L. Pentelute
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| Open Access
Stereospecific Si-C coupling and remote control of axial chirality by enantioselective palladium-catalyzed hydrosilylation of maleimides
Catalytic asymmetric hydrosilylation of internal alkenes has proven elusive due to more favourable double bond reduction or isomerization. Here, the authors show an enantioselective Si-C coupling by hydrosilylation of activated alkenes using a palladium/phosphoramidite catalyst affording axially chiral succinimides.
- Xing-Wei Gu
- , Yu-Li Sun
- & Li-Wen Xu
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Article
| Open Access
Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones
Combining genome mining and heterologous expression in a genetically tractable host can lead to bioactive natural products discovery and production. Here, the authors employ this strategy for new decalin-containing diterpenoid pyrenes production by expressing native, extended, and shunt pathways in Aspergillus oryzae.
- Kento Tsukada
- , Shono Shinki
- & Teigo Asai
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Article
| Open Access
A general strategy for diversifying complex natural products to polycyclic scaffolds with medium-sized rings
Derivatization of natural products is a powerful approach to generate new molecules for biological screenings. Here, the authors employ C-H oxidation and ring expansion methods for the preparation of a library of medium-sized ring skeleta, which occupy a unique chemical space based on chemoinformatic analysis.
- Changgui Zhao
- , Zhengqing Ye
- & Weiping Tang
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Article
| Open Access
Development of a high-throughput strategy for discovery of potent analogues of antibiotic lysocin E
The depsipeptide Lysocin E has antibacterial activity against methicillin-resistant Staphylococcus aureus. Here, the authors developed a high-throughput one-bead-on-compound method for the synthesis and screening lysocin E derivatives, with several hits being more active than the parent compound.
- Hiroaki Itoh
- , Kotaro Tokumoto
- & Masayuki Inoue
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Article
| Open Access
Marrying chemistry with biology by combining on-chip solution-based combinatorial synthesis and cellular screening
High-throughput cell-based screening of compound libraries is utilised in drug development; however, a lack of compatible methods limits direct synthesis and testing. Here, the authors present a diverse chip based synthesis system which can be combined with cell screening and demonstrate the application.
- Maximilian Benz
- , Mijanur R. Molla
- & Pavel A. Levkin
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Article
| Open Access
A multi-substrate screening approach for the identification of a broadly applicable Diels–Alder catalyst
Investigation of a reaction scope usually starts with the optimization for a model substrate. Here, the authors apply a time-efficient multi-substrate screening approach to identify a general organocatalyst for the Diels–Alder reaction of cyclopentadiene with α,β-unsaturated aldehydes.
- Hyejin Kim
- , Gabriela Gerosa
- & Benjamin List
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Article
| Open Access
A diversity-oriented rhodamine library for wide-spectrum bactericidal agents with low inducible resistance against resistant pathogens
Preparation of xanthene-containing compounds has been limited due to structural bias existing methods pose. Here, the authors developed a mild, diversity-oriented method for rhodamines synthesis, leading to the finding of compounds with antibacterial potency against a variety of bacterial species.
- Xiao Luo
- , Liujia Qian
- & Youjun Yang
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Article
| Open Access
Iridium-catalyzed reductive Ugi-type reactions of tertiary amides
Chemical transformation of amides is normally occurring under harsh conditions. Here, the authors report a mild iridium-catalyzed reductive Ugi-type coupling of tertiary amides, isocyanides and (thio)acetic acid or trimethylsilyl azide to give homologous, bioactive amine products.
- Lan-Gui Xie
- & Darren J. Dixon
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Article
| Open Access
Elucidation of the origin of chiral amplification in discrete molecular polyhedra
The sergeants-and-soldiers effect, in which a few chiral units induce chirality in a large number of achiral molecules, is difficult to quantify at the molecular level. Here, the authors devise an elegant strategy—combining theory and a system of pure organic polyhedra with chiral and achiral vertices—to understand the mechanism of chiral amplification in discrete molecular assemblies.
- Yu Wang
- , Hongxun Fang
- & Xiaoyu Cao
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Article
| Open Access
Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
Encoded Library Technology (ELT) has streamlined the identification of chemical ligands for protein targets in drug discovery. Here, the authors optimize the ELT approach to screen multiple proteins in parallel and identify promising targets and antibacterial compounds forS. aureus, A. baumannii and M. tuberculosis.
- Carl A. Machutta
- , Christopher S. Kollmann
- & Ghotas Evindar
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Article
| Open Access
Target guided synthesis using DNA nano-templates for selectively assembling a G-quadruplex binding c-MYC inhibitor
Identification of inhibitors can be accelerated by using the target as a template for ligand formation. Here the authors show that DNA-functionalised magnetic nanoparticles guide templating of G-quadruplex bindingc-MYCinhibitors from an array of building blocks, and can be isolated by magnetic decanting.
- Deepanjan Panda
- , Puja Saha
- & Jyotirmayee Dash
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Article
| Open Access
Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction
Diversity-oriented synthesis is useful for generating complex molecular structures occupying diverse molecular space. Here the authors report a strategy to access libraries of privileged heterocyclic structures, and furthermore identify an inhibitor of LRS–RagD protein–protein interaction.
- Jonghoon Kim
- , Jinjoo Jung
- & Seung Bum Park
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Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo
Inhibiting the interaction between the membrane protein P-selectin and its ligand PSGL-1 is thought to block inflammation. Here the authors report an efficient stereoselective synthesis for PSGL-1 glycopeptide mimics and show that these compounds inhibit PSGL-1/P-selectin in vitro and in vivo.
- Venkata R. Krishnamurthy
- , Mohammed Y. R. Sardar
- & Elliot L. Chaikof
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Article
| Open Access
Combinatorial targeting and discovery of ligand-receptors in organelles of mammalian cells
Phage display screening can unravel protein–protein interactions, but its application has been mainly restricted to the cell surface. Here, a phage-based reagent is introduced that allows the targeting of combinatorial peptides to cell organelles, providing a tool for the discovery of intracellular ligand-receptors.
- Roberto Rangel
- , Liliana Guzman-Rojas
- & Wadih Arap
Targeted sampling of natural product space to identify bioactive natural product-like polyketide macrolides