Article
|
Open Access
Featured
-
-
Article
| Open AccessA modular biomimetic strategy for the synthesis of macrolide P-glycoprotein inhibitors via Rh-catalyzed C-H activation
One strategy to address multidrug resistance in cancer is the development of modular methods to access bioactive scaffolds. Here, the authors report a Rh(III)-catalyzed carboxylic acid-directed C(sp2)−H allylation and apply it to the modular synthesis of (Z)-allylic macrolides which enhance antitumoral drug activity.
- Lu Chen
- , Haitian Quan
- & Weibo Yang
-
Article
| Open AccessSynthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy
Bryostatin 1 is a unique therapeutic lead, however its scarce natural sources have hampered its use in treatment of human disease. Here, the authors use a scalable synthesis of bryostatin 1 to make close-in analogs which potently induce increased cell surface expression holding potential for immunotherapy.
- Clayton Hardman
- , Stephen Ho
- & Paul A. Wender
-
Article
| Open AccessA general 11C-labeling approach enabled by fluoride-mediated desilylation of organosilanes
Convenient and fast methods to introduce 11C into organic molecules are of great help for molecular imaging studies. Here, the authors developed an efficient incorporation of [11C]CO2 and [11C]CH3I into molecules via a fluoride-mediated desilylation process.
- Wenchao Qu
- , Bao Hu
- & Julie Urgiles
-
Article
| Open AccessNucleophilic trifluoromethoxylation of alkyl halides without silver
Trifluoromethyl ethers are important bioactive targets in pharmaceuticals and agrochemicals, however, their synthesis is often not straightforward. Here, the authors disclose a reagent for the nucleophilic trifluoromethoxylation of alkyl halides without silver and under mild conditions.
- Yan Li
- , Yang Yang
- & Pingping Tang
-
Article
| Open AccessElucidating target specificity of the taccalonolide covalent microtubule stabilizers employing a combinatorial chemical approach
Taccalonolide microtubule stabilizers covalently bind β-tubulin and overcome taxane resistance mechanisms. Here, the authors synthesized fluorogenic taccalonolide probes and investigated the specificity of taccalonolide binding to β-tubulin and the molecular interactions between drug and target,
- Lin Du
- , Samantha S. Yee
- & April L. Risinger
-
Article
| Open AccessDe novo generation of hit-like molecules from gene expression signatures using artificial intelligence
High quality hit identification remains a considerable challenge in de novo drug design. Here, the authors train a generative adversarial network with transcriptome profiles induced by a large set of compounds, enabling it to design molecules that are likely to induce desired expression profiles.
- Oscar Méndez-Lucio
- , Benoit Baillif
- & Joerg Wichard
-
Article
| Open AccessSmall molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer
While biologics have been successfully applied in TNF antagonist treatments, there are no clinically approved small molecules that target TNF. Here, the authors discover potent small molecule inhibitors of TNF, elucidate their molecular mechanism, and demonstrate TNF inhibition in vitro and in vivo.
- James O’Connell
- , John Porter
- & Alastair Lawson
-
Article
| Open AccessCombining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness
Trypanosoma brucei relies on uptake and conversion of purines from the host, which constitutes a potential drug target. Here, Hulpia et al. combine structural elements from known trypanocidal nucleoside analogues and develop a potent trypanocide with curative activity in animal models of acute and late stage sleeping sickness.
- Fabian Hulpia
- , Dorien Mabille
- & Serge Van Calenbergh
-
Article
| Open AccessFunctionalized azetidines via visible light-enabled aza Paternò-Büchi reactions
The Aza Paternò-Büchi reaction is arguably among the most direct approaches to functionalized azetidines, which are common medicinal scaffolds. Here, the authors report a mild and selective visible light-enabled intramolecular aza Paternò-Büchi reaction yielding bicyclic azetidines in high yields and diastereoselectivity.
- Marc R. Becker
- , Alistair D. Richardson
- & Corinna S. Schindler
-
Article
| Open AccessVastly extended drug release from poly(pro-17β-estradiol) materials facilitates in vitro neurotrophism and neuroprotection
Currently there are no therapeutics for long lasting central nervous system injuries, that can address the complex injury cascade that develops over years. Here the authors report biomaterial scaffolds that release 17β-estradiol (E2) at nanomolar concentrations over the course of 1–10 years via slow hydrolysis in vitro.
- Anthony R. D’Amato
- , Devan L. Puhl
- & Edmund F. Palermo
-
Article
| Open AccessHigh-potency ligands for DREADD imaging and activation in rodents and monkeys
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a powerful tool for neuroscience, but the standard DREADD ligand, CNO, has significant drawbacks. Here the authors report two novel high-potency DREADD ligands and a novel DREADD radiotracer for imaging purposes.
- Jordi Bonaventura
- , Mark A. G. Eldridge
- & Michael Michaelides
-
Article
| Open AccessHarnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents
FK506 is a potential antifungal compound that inhibits calcineurin, but it also has immunosuppressive activity. Here, Juvvadi et al. report the structure of FK506 in complex with the FK506-binding protein FKPB12 and calcineurin, and design a less immunosuppresive FK506 analog with antifungal activity in mice.
- Praveen R. Juvvadi
- , David Fox III
- & William J. Steinbach
-
Article
| Open AccessGram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
The presence of the unnatural amino acid l-allo-enduracidine in the cyclic scaffold of teixobactin complicates its total synthesis. Here, the authors developed a convergent strategy for the scalable synthesis teixobactin and found two potent analogous.
- Yu Zong
- , Fang Fang
- & Yu Rao
-
Article
| Open AccessDevelopment 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
-
Article
| Open AccessMarrying 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
-
Article
| Open AccessCatalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs
Phthalidyl esters, commonly used prodrug moieties, are mostly prepared as a racemate. Here, the authors report an N-heterocylcic carbene-catalysed enantioselective acetalization of carboxylic acids and dialdehydes to give phthalidyl esters in high yields with good enantioselectivity.
- Yingguo Liu
- , Qiao Chen
- & Yonggui Robin Chi
-
Article
| Open AccessRapid one-step 18F-radiolabeling of biomolecules in aqueous media by organophosphine fluoride acceptors
The synthesis of 18F-labeled positron emission tomography (PET) tracers is difficult and typically requires anhydrous conditions. Here, the authors developed organophosphine precursors that allow for quick, high-yield synthesis of 18F-labeled probes in either organic solvents or aqueous media.
- Huawei Hong
- , Lei Zhang
- & Zijing Li
-
Article
| Open AccessPeptide-oligourea hybrids analogue of GLP-1 with improved action in vivo
The peptide hormone GLP-1 has the potential to be a remedy for diabetes type II, yet is unstable. Here, the authors synthesized α-peptide-oligourea hybrid analogues of GLP-1 some of which showing significantly prolonged activity in vivo.
- Juliette Fremaux
- , Claire Venin
- & Sébastien R. Goudreau
-
Article
| Open AccessA 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
-
Article
| Open AccessStructure and inhibition mechanism of the catalytic domain of human squalene epoxidase
Squalene epoxidase (SQLE) is a key enzyme in cholesterol biosynthesis and is a target for hypercholesteremia and cancer drug development. Here the authors present the crystal structures of the human SQLE catalytic domain alone and bound with small molecule inhibitors, which will facilitate the development of next-generation SQLE inhibitors.
- Anil K. Padyana
- , Stefan Gross
- & Gromoslaw A. Smolen
-
Article
| Open AccessThe transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation
The oncogene STAT5 is involved in cancer cell proliferation. Here, the authors use STAT5 protein to assemble its own small molecule inhibitors via Mannich ligation (three-component-reactions) and show that the resultant ligands can inhibit the proliferation of cancer cells in a mouse model.
- Ee Lin Wong
- , Eric Nawrotzky
- & Jörg Rademann
-
Article
| Open AccessLattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry
Temsavir, a compound that inhibits HIV entry by binding envelope (Env), is currently in clinical development. Here, Lai et al. identify a more than 10-fold improved compound and, using lattice engineering, obtain crystal structures that give insights into improved inhibition between small molecules and Env.
- Yen-Ting Lai
- , Tao Wang
- & Peter D. Kwong
-
Article
| Open AccessIndustrial scale high-throughput screening delivers multiple fast acting macrofilaricides
Parasitic nematodes causing onchocerciasis and lymphatic filariasis rely on a bacterial endosymbiont, Wolbachia, which is a validated therapeutic target. Here, Clare et al. perform a high-throughput screen of 1.3 million compounds and identify 5 chemotypes with faster kill rates than existing anti-Wolbachia drugs.
- Rachel H. Clare
- , Catherine Bardelle
- & Stephen A. Ward
-
Article
| Open AccessDiscovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia
High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.
- Adriana E. Tron
- , Matthew A. Belmonte
- & Alexander W. Hird
-
Article
| Open AccessEfflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation
Antifungal resistance due to upregulation of efflux pumps is common in Candida albicans. Here, the authors show that conjugation with mitochondria-targeting triphenylphosphonium cation can enhance or restore the antifungal activity of potential efflux pump substrates.
- Wenqiang Chang
- , Jun Liu
- & Hongxiang Lou
-
Article
| Open AccessMultidirectional desymmetrization of pluripotent building block en route to diastereoselective synthesis of complex nature-inspired scaffolds
Methods enabling the synthesis of diverse collections of nature-inspired compounds with potential medicinal use are sought after in drug design. Here, the authors report a build/couple/pair strategy to efficiently construct chiral polycyclic scaffolds and show their diversification for drug discovery screening.
- Vunnam Srinivasulu
- , Paul Schilf
- & Taleb H. Al-Tel
-
Article
| Open AccessDesign and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1
Step-economical and efficient syntheses of Spongistatin 1 analogs are desirable for the development of potent anti-proliferative agents. Here, the authors report a 22-step synthesis of a D-ring modified Spongistatin 1 analog with retained picomolar potency among a group of C(15) ester derivatives.
- Linda M. Suen
- , Makeda A. Tekle-Smith
- & James L. Leighton
-
Article
| Open AccessA therapeutic approach to pantothenate kinase associated neurodegeneration
Mutations in pantotenate kinase (PANK) cause neurodegneration. Here the authors carry out achemical screen and identify a PANK activator that is orally available, crosses the blood brain barrierand show that it effecttive in improving pathology and life span in a mouse model of the disease.
- Lalit Kumar Sharma
- , Chitra Subramanian
- & Suzanne Jackowski
-
Article
| Open AccessHigh-resolution NMR studies of antibiotics in cellular membranes
Antibiotics that target the peptidoglycan precursor lipid II are promising templates for next-generation antibiotics. Here authors use solid-state NMR and monitor lipid II-binding antibiotics, such as nisin, directly in cell membranes.
- João Medeiros-Silva
- , Shehrazade Jekhmane
- & Markus Weingarth
-
Article
| Open AccessClopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H2S biomedicine
Hydrogen sulphide (H2S) is a gaseous signalling molecule, which has shown therapeutic value. Here, the authors show that a thioenol metabolite of the antithrombotic drug clopidogrel is an efficient H2S donor and masked thioenols can be linked to existing compounds to develop H2S-releasing agents.
- Yaoqiu Zhu
- , Elkin L. Romero
- & Bin Geng
-
Article
| Open AccessEndogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase
Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.
- Helmut Pein
- , Alexia Ville
- & Andreas Koeberle
-
Article
| Open AccessTotal synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens
Albomycins are promising drug candidates for the treatment of bacterial infections. Here, the authors describe the total syntheses of albomycins δ1, δ2, and ε, and evaluate their antimicrobial activity, identifying albomycin δ2 as a strong agent against S. pneumoniae and S. aureus infections.
- Zihua Lin
- , Xiaobo Xu
- & Yun He
-
Article
| Open AccessSmall molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment
Intracellular antibodies can inhibit disease-relevant protein interactions, but inefficient cellular uptake limits their utility. Using a RAS-targeting intracellular antibody as a screening tool, the authors here identify small molecules that inhibit RAS-effector interactions and readily penetrate cells.
- Camilo E. Quevedo
- , Abimael Cruz-Migoni
- & Terence H. Rabbitts
-
Article
| Open AccessGlutamic acid–valine–citrulline linkers ensure stability and efficacy of antibody–drug conjugates in mice
The valine-citrulline dipeptide, which is used as a cleavable linker for antibody-drug conjugates, is instable in mouse plasma. Here, the authors developed a glutamic acid–valine–citrulline tripeptide sequence as a stable alternative that still is susceptible to cathepsin-mediated cleavage.
- Yasuaki Anami
- , Chisato M. Yamazaki
- & Kyoji Tsuchikama
-
Article
| Open AccessChemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice
Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells. Here, the authors report the development and in vivo validation of a non-internalising ADC with the capacity to target cancer cells and release its therapeutic cargo extracellularly via a chemical trigger.
- Raffaella Rossin
- , Ron M. Versteegen
- & Marc S. Robillard
-
Article
| Open AccessSubstrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site
Sialic acid transporters (SiaT) are required for sialic acid uptake in a number of human pathogens and are of interest as targets for antimicrobial drug development. Here the authors present the substrate bound SiaT structure from the uropathogen Proteus mirabilis and provide insights into the mechanism of sialic acid transport.
- Weixiao Y. Wahlgren
- , Elin Dunevall
- & Rosmarie Friemann
-
Article
| Open AccessScalable synthesis enabling multilevel bio-evaluations of natural products for discovery of lead compounds
Isodon diterpenoids, promising anti-cancer agents found in certain tropical plants, are difficult to obtain. Here, the authors developed a synthetic strategy to synthesise several different members of this group, including neolaxiflorin L which emerged from this study as a promising drug candidate.
- Lizhi Zhu
- , Wenjing Ma
- & Chi-Sing Lee
-
Article
| Open AccessImpaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor
Dopamine receptor agonists are used for the treatment of various psychiatric diseases. Here, the authors screen approximately three million compounds and identify a novel class of D1R agonists that do not have a catechol scaffold and possess promising pharmacokinetic properties.
- David L. Gray
- , John A. Allen
- & Michael D. Ehlers
-
Correspondence
| Open AccessCorrespondence: Compound 17b and formyl peptide receptor biased agonism in relation to cardioprotective effects in ischaemia-reperfusion injury
- Agostino Cilibrizzi
-
Article
| Open AccessA small molecule inhibitor of Rheb selectively targets mTORC1 signaling
Aberrant mTORC1 signaling is linked to several chronic diseases. Here, the authors develop a small molecule inhibitor that binds the small G-protein Rheb and selectively blocks mTORC1 signaling, holding potential for therapeutic applications.
- Sarah J. Mahoney
- , Sridhar Narayan
- & Eddine Saiah
-
Article
| Open AccessStructure-guided design of an Hsp90β N-terminal isoform-selective inhibitor
The molecular chaperone Hsp90 oversees the folding of many proteins associated with cancer progression but existing small-molecule inhibitors of this pathway are not isoform-selective. Here, the authors rationally design an Hsp90 inhibitor that displays high selectivity for the Hsp90β isoform.
- Anuj Khandelwal
- , Caitlin N. Kent
- & Brian S. J. Blagg
-
Article
| Open AccessTargeted NUDT5 inhibitors block hormone signaling in breast cancer cells
NUDIX hydrolases are an important family of nucleotide-metabolizing enzymes. Here, the authors identify potent, small molecule inhibitors of NUDT5, which is implicated in ADP-ribose and 8-oxo-guanine metabolism, and confirm its role in gene regulation and proliferation in breast cancer cells.
- Brent D. G. Page
- , Nicholas C. K. Valerie
- & Thomas Helleday
-
Article
| Open AccessProtein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria
The antibiotic vancomycin inhibits bacterial cell wall synthesis by binding to a membrane-associated precursor. Here, Blaskovich et al. synthesize vancomycin derivatives containing lipophilic peptide moieties that enhance membrane affinity and in vivo activities against glycopeptide-resistant strains.
- Mark A. T. Blaskovich
- , Karl A. Hansford
- & Matthew A. Cooper
-
Article
| Open AccessHighly enantioselective catalytic synthesis of chiral pyridines
Chiral pyridines are valuable building blocks in medicinal chemistry applications. Here, the authors report the copper-catalysed Lewis acid-assisted asymmetric alkylation of β-substituted alkenyl pyridines with Grignard reagents affording chiral pyridines with excellent enantioselectivity.
- Ravindra P. Jumde
- , Francesco Lanza
- & Syuzanna R. Harutyunyan
-
Article
| Open AccessStructure of human immunoproteasome with a reversible and noncompetitive inhibitor that selectively inhibits activated lymphocytes
Immunoproteasome selective inhibitors might lead to less toxic drugs for treatment of multiple myeloma and graft rejection. Here, the authors develop immunoproteasome specific asparagine-ethylenediamine (AsnEDA)-based inhibitory compounds, demonstrate their efficacy and present the AsnEDA bound immunoproteasome cryo-EM structure.
- Ruda de Luna Almeida Santos
- , Lin Bai
- & Gang Lin
-
Article
| Open AccessDiastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles using both aldonitrones and ketonitrones
Chiral spirocyclic compounds are important structural motifs for drug discovery. Here, the authors report a synthetic route to spirocycles based on enantioselective cycloaddition of activated spirocyclopropyl oxindoles, which act as donor-acceptor cyclopropanes.
- Peng-Wei Xu
- , Jia-Kuan Liu
- & Jian Zhou
-
Article
| Open AccessAssay interference and off-target liabilities of reported histone acetyltransferase inhibitors
A substantial obstacle in basic research is the use of poorly validated tool compounds with purported useful biological functions. Here, the authors systematically profile widely used histone acetyltransferase inhibitors and find that the majority are nonselective interference compounds.
- Jayme L. Dahlin
- , Kathryn M. Nelson
- & Michael A. Walters
-
Article
| Open AccessOrganocatalytic enantio- and diastereoselective cycloetherification via dynamic kinetic resolution of chiral cyanohydrins
Enantioselective synthesis of six-membered oxacycles with multiple stereogenic centres is essential for the discovery of new therapeutic agents. Here the authors show organocatalytic cycloetherification for the highly enantio- and diastereoselective synthesis of tetrahydropyrans.
- Naoki Yoneda
- , Yuki Fujii
- & Seijiro Matsubara
-
Article
| Open AccessA potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation
Cullins are central components of the ubiquitin-proteosome system and are activated via a neddylation process mediated by the DCN1–UBC12 complex. Here, the authors develop a small molecule inhibitor of the DCN1–UBC12 interaction that specifically blocks cullin 3 neddylation and can be used to probe the cellular function of cullin 3.
- Haibin Zhou
- , Jianfeng Lu
- & Shaomeng Wang