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| Open AccessSmall molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
Type 2 diabetes is associated with insulin resistance, impaired insulin secretion and liver steatosis. Here the authors report a proof-of-concept study for small molecule SWELL1 modulators as a therapeutic approach to treat diabetes and associated liver steatosis by enhancing systemic insulin-sensitivity and insulin secretion in mice.
- Susheel K. Gunasekar
- , Litao Xie
- & Rajan Sah
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Article
| Open AccessDifferential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate
Liu et al. report structures of human sphingosine 1-phosphate (S1P) receptor 1 (S1P1) in complex with Gi and S1P or the multiple sclerosis (MS) drug Siponimod, as well as human lysophosphatidic acid (LPA) receptor 1 (LPA1) in complex with Gi and LPA, revealing distinct conformations of the lysophospholipids interacting with their cognate GPCRs.
- Shian Liu
- , Navid Paknejad
- & Xin-Yun Huang
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Article
| Open AccessDecisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors
The molecular determinants of the residence time of a small molecule inhibitor at its target protein are not well understood. Here, Pantsar et al. show that the target protein’s conformational stability and solvent exposure are key factors governing the target residence time of kinase inhibitors.
- Tatu Pantsar
- , Philipp D. Kaiser
- & Stefan A. Laufer
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Article
| Open AccessA propolis-derived small molecule ameliorates metabolic syndrome in obese mice by targeting the CREB/CRTC2 transcriptional complex
Disruption of CREB/CRTC2, a key gluconeogenic transcriptional complex, has been shown to ameliorate insulin resistance in mice. Here, the authors show that the inhibitor artipllin C and the synthetic compound A57, which presents with higher inhibitory activity, improve insulin sensitivity in obese mice by inhibiting CREB-CRTC2 interaction.
- Yaqiong Chen
- , Jiang Wang
- & Yi Liu
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Article
| Open AccessPyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps
Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, the authors identify pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through allosteric inhibition of its primary RND transporter.
- Coline Plé
- , Heng-Keat Tam
- & Ruben C. Hartkoorn
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Article
| Open AccessSynthetic prodrug design enables biocatalytic activation in mice to elicit tumor growth suppression
Considering the intrinsic toxicities of transition metals, their incorporation into drug therapies must operate at minimal amounts while ensuring adequate catalytic activity within complex biological systems. This study investigates the design of synthetic prodrugs that not only can be tuned to be harmless, but are robustly transformed in vivo to reach therapeutically relevant levels.
- Igor Nasibullin
- , Ivan Smirnov
- & Katsunori Tanaka
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Article
| Open AccessSliding of HIV-1 reverse transcriptase over DNA creates a transient P pocket – targeting P-pocket by fragment screening
Here the authors observe a transient P-pocket created when HIV reverse transcriptase slides over DNA substrate, identify fragments targeting this pocket, and develop a cryo-EM platform for lead optimization.
- Abhimanyu K. Singh
- , Sergio E. Martinez
- & Kalyan Das
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Article
| Open AccessFluorinated rhamnosides inhibit cellular fucosylation
Aberrant expression of fucosylated glycans has been linked to several disease states. Control of fucose expression on live cells is needed to aid research and therapy development. Here the authors report on the development of a class of fucosylation metabolic prodrug inhibitors and demonstrated inhibition of cellular fucosylation.
- Johan F. A. Pijnenborg
- , Emiel Rossing
- & Thomas J. Boltje
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Article
| Open AccessDevelopment of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,
Simultaneous targeting of BCL-xL and BCL-2 is an attractive approach for cancer treatment. Based on information gained by computational structure modelling, the authors develop a PROTAC that induces degradation of both BCL-xL and BCL-2 and effectively targets BCL-xL/2-dependent leukaemia cells.
- Dongwen Lv
- , Pratik Pal
- & Daohong Zhou
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Article
| Open AccessEfficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors
Bleeding complications limits the use of effective antithrombotics therapeutics. Here, the authors developed next-generation direct thrombin inhibitors with low bleeding risks as safe peri-percutaneous coronary intervention anticoagulants when used in combination with antiplatelets.
- Cho Yeow Koh
- , Norrapat Shih
- & Mark Y. Chan
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Article
| Open AccessStructure of PDE3A–SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells
Anagrelide, nauclefine and DNMDP induce apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). Here, the authors present the cryo-EM structures of PDE3A-SLFN12 complexes with these compounds as molecular glues. Based on the complex structure, they developed an anagrelide analog that shows a higher potency in inducing apoptosis in cultured cells and also promotes tumor growth inhibition in tumor xenografts, which is of interest for cancer drug development.
- Jie Chen
- , Nan Liu
- & Xiaodong Wang
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Article
| Open AccessModular ketal-linked prodrugs and biomaterials enabled by organocatalytic transisopropenylation of alcohols
Isopropenyl ethers (IPPEs) are essential intermediates for obtaining ketal-based prodrugs and biomaterials, but traditional approaches for their synthesis are limited by poor functional group compatibility and harsh reaction conditions. Here, the authors report an organocatalytic transisopropenylation approach for IPPE synthesis in mild reaction conditions and with wide range of substrates, and use it to prepare acid-sensitive ketal-linked prodrugs and biomaterials.
- Na Yu
- , Yang Xu
- & Shutao Guo
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Article
| Open AccessCellular model system to dissect the isoform-selectivity of Akt inhibitors
Elucidating specific effects of protein kinase Akt isoforms remains challenging. Here, the authors establish an Akt isoform-dependent cellular model system and use it, together with X-ray crystallography and structure-based ligand design, to develop isoform-selective covalent-allosteric Akt inhibitors
- Lena Quambusch
- , Laura Depta
- & Daniel Rauh
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Article
| Open AccessThe enzymatic activity of inositol hexakisphosphate kinase controls circulating phosphate in mammals
Inositol hexakisphosphate kinase (IP6K) is involved in diverse cellular signalling pathways, but the physiological roles of IP6K in vivo remain unknown in mammals. Here, the authors show that the enzymatic activity of IP6K is essential for phosphate regulation in vivo.
- Yusuke Moritoh
- , Shin-ichi Abe
- & Masanori Watanabe
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Article
| Open AccessCompounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease
This study describes a class of small molecule compounds that promote ABCA1-dependent cholesterol efflux via a non-transcriptional mechanism, the identification of the molecular target by a chemical biology approach, and the potential of these agents for the treatment of chronic kidney diseases and potentially other diseases where lipid accumulation drives disease progression.
- Matthew B. Wright
- , Javier Varona Santos
- & Alessia Fornoni
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Article
| Open AccessTetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists
Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.
- Yi Yang
- , Adam Csakai
- & Hang Yin
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Article
| Open AccessSelective targeting of ligand-dependent and -independent signaling by GPCR conformation-specific anti-US28 intrabodies
Various GPCRs display constitutive ligand-independent activity, but it remains unclear whether ligand-dependent and -independent conformations differ. Here the authors demonstrate the recognition and blocking of G protein recruitment of either the ligand-bound active, or the constitutively active apo-conformation of the viral GPCR US28 by different nanobodies that target similar intracellular loops of the receptor.
- Timo W. M. De Groof
- , Nick D. Bergkamp
- & Martine J. Smit
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Article
| Open AccessA novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke
Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.
- Toshiko Yamazawa
- , Takuya Kobayashi
- & Takashi Murayama
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Article
| Open AccessProtein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function
Amyloid aggregation of mutant p53 contributes to its loss of tumor suppressor function and oncogenic gain-of-function. Here, the authors use a protein mimetic to abrogate mutant p53 aggregation and rescue p53 function, which inhibits cancer cell proliferation in vitro and halts tumor growth in vivo.
- L. Palanikumar
- , Laura Karpauskaite
- & Mazin Magzoub
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Review Article
| Open AccessMining and unearthing hidden biosynthetic potential
Natural products are an important source of bioactive compounds and have versatile applications in different fields, but their discovery is challenging. Here, the authors review the recent developments in genome mining for discovery of natural products, focusing on compounds from unconventional microorganisms and microbiomes.
- Kirstin Scherlach
- & Christian Hertweck
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Article
| Open AccessSite selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy
Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy.
- Srijita Bhowmik
- , Juraj Galeta
- & Dalibor Sames
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Article
| Open AccessIdentification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease
SARS-CoV-2 3CL protease (3CLpro) is essential for coronavirus replication and of great interest as an antiviral drug target. Here, the authors show that the naturally occurring flavonoid myricetin is a non-peptidomimetic and covalent inhibitor of 3CLpro, and they solve crystal structures of 3CLpro with myricetin and derivatives, which reveal that the pyrogallol group covalently modifies the catalytic cysteine.
- Haixia Su
- , Sheng Yao
- & Yechun Xu
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Article
| Open AccessLipophilic nanocrystal prodrug-release defines the extended pharmacokinetic profiles of a year-long cabotegravir
Here, the authors provide a mechanism for an improved version of a nanoformulated myristoylated prodrug of cabotegravir (CAB), named NM2CAB, and its bioavailability, stability and pharmacokinetics in mice and rats performed in independent academic and a contracted research labs, suggesting that the extended half-life of the prodrug is not a property of enzymatic hydrolysis but rather release or dissolution of the prodrug from the nanocrystal.
- Nagsen Gautam
- , JoEllyn M. McMillan
- & Yazen Alnouti
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Article
| Open AccessExploring protein hotspots by optimized fragment pharmacophores
Fragment-based drug discovery employs screening of small polar compounds typically exhibiting low affinity towards protein targets. Here, the authors combine the use of protein-based binding pharmacophores with the theory of protein hotspots to develop a design protocol for fragment libraries, called SpotXplorer, and validate their approach on common and emerging drug targets.
- Dávid Bajusz
- , Warren S. Wade
- & György M. Keserű
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Article
| Open AccessInhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives
Ebselen is an organoselenium drug that inhibits the SARS-CoV-2 main protease (Mpro). Here, the authors co-crystallised Mpro with ebselen and an ebselen derivative and observed an enzyme bound organoselenium covalent adduct in the crystal structures, which was also confirmed by mass spectrometry analysis.
- Kangsa Amporndanai
- , Xiaoli Meng
- & S. Samar Hasnain
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Article
| Open AccessPolymer-free corticosteroid dimer implants for controlled and sustained drug delivery
Polymer-based systems are often considered a necessity for controlled drug delivery, but have well-known limitations. Here, the authors report on drug delivery implants formed solely from corticosteroid dimers, which demonstrate controlled release and overcome many of the challenges of polymer-based systems.
- Kyle Battiston
- , Ian Parrag
- & Wendy Naimark
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Article
| Open AccessDiscovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity
The histone methyltransferase ASH1L plays a role in various diseases, including cancer, and has been validated as a therapeutic target; however, no inhibitors of ASH1L have been reported. Here the authors present small molecule inhibitors of ASH1L and demonstrate their on-target activity in leukemia cells and a mouse model of leukemia.
- David S. Rogawski
- , Jing Deng
- & Jolanta Grembecka
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Article
| Open AccessSelective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity
Activation of cullin-RING ligases can be inhibited by targeting DCN1, but selective DCN1 inhibitors with in vivo activity are lacking. Here, the authors develop covalent DCN1 inhibitors that selectively and potently inhibit cullin-3 activation and downstream functions in cells and in mice.
- Haibin Zhou
- , Jianfeng Lu
- & Shaomeng Wang
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Article
| Open AccessModification of N-terminal α-amine of proteins via biomimetic ortho-quinone-mediated oxidation
Methods for selective modification of the N-terminus of proteins are of high interest, but mostly require specific amino acid residues. Here, the authors report a selective and fast method for N-terminal modification of proteins based on quinone-mediated oxidation of the alpha-amine to aldehyde or ketone, and apply it to diverse proteins.
- Siyao Wang
- , Qingqing Zhou
- & Ping Wang
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Article
| Open AccessStructure-based design of a Cortistatin analogue with immunomodulatory activity in models of inflammatory bowel disease
Inflammatory bowel disease is caused by chronic inflammation of the gastrointestinal tract and disturbed immune responses. Here the authors present examination of Cortistatin analogues that display enhanced half-life stability whilst maintaining immunomodulatory functionality.
- Álvaro Rol
- , Toni Todorovski
- & Maria J. Macias
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Article
| Open AccessFast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice
Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model.
- Iain W. McNae
- , James Kinkead
- & Malcolm D. Walkinshaw
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Article
| Open AccessPotent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds
The mechanism of DNA gyrase inhibitor stabilization of single-strand DNA cleavage breaks by DNA gyrase has been hypothetical. Here, the authors show experimental evidence of the mechanism using a library of inhibitors with improved binding and employ crystal analysis to show bifurcated halogen bonding.
- Anja Kolarič
- , Thomas Germe
- & Marko Anderluh
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Article
| Open AccessThioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359
FR900359 (FR) is a Gq protein inhibitor depsipeptide isolated from an uncultivable plant endosymbiont and synthesized by non-ribosomal peptide synthetases. Here, the authors discover a cultivable bacterial FR producer and show that FrsA thioesterase domain catalyses intermolecular transesterification of the FR side chain to the depsipeptide core during biosynthesis, improving Gq inhibition properties.
- Cornelia Hermes
- , René Richarz
- & Max Crüsemann
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Article
| Open AccessNature-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 AccessDesigned CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting
The development of specific anti-cytokine/chemokine therapeutic strategies for atherosclerotic disease is challenging. Here, the authors have designed a peptide-based ectodomain mimic of the chemokine receptor CXCR4 that selectively targets MIF but not CXCL12 and blocks experimental atherosclerosis in vivo.
- Christos Kontos
- , Omar El Bounkari
- & Jürgen Bernhagen
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Article
| Open AccessAdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis
Nonalcoholic steatohepatitis (NASH) and associated liver fibrosis have limited therapy options. Here the authors report a novel adiponectin-based dual agonist for adiponectin receptors 1 and 2 with a longer half-life, and show that it ameliorates NASH and liver fibrosis in mouse models.
- Hongjiao Xu
- , Qian Zhao
- & Xianxing Jiang
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Article
| Open AccessA 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 AccessResensitizing carbapenem- and colistin-resistant bacteria to antibiotics using auranofin
Multi-drug resistant pathogens remain a serious public health threat. Here, Sun and colleagues identify a role for auranofin, which is normally used as a drug for rheumatoid arthritis, for reversing antibiotic resistance to carbapenem and colistin.
- Hongzhe Sun
- , Qi Zhang
- & Hongyan Li
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Article
| Open AccessDiscovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library
The strong hemolytic activity and mammalian cytotoxicity of gramicidin A, a peptide antibiotic, has hindered its non-topical clinical application. Here, the authors report a high-throughput strategy for the discovery of gramicidin A analogues with altered biological activity profiles.
- Yuri Takada
- , Hiroaki Itoh
- & Masayuki Inoue
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Article
| Open AccessPharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy
Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here, the authors generate single-drug nanoparticles by hybridising lysomotropic detergents and the bisaminoquinoline-based autophagy inhibitor, and show their therapeutic potential as autophagy-inhibition based combination therapy.
- Zhao Ma
- , Jin Li
- & Yuanpei Li
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Article
| Open AccessA stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A
The Neisseria meningitidis serogroup A capsular polysaccharide (MenA CPS) is a component of commercial vaccines, but is unstable. Here, the authors generate glycomimetic oligomers that demonstrate higher stability than their natural counterparts and induce protective antibodies in mice.
- Jacopo Enotarpi
- , Marta Tontini
- & Roberto Adamo
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Article
| Open AccessEnhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry
PROTACs have emerged as promising therapeutic agents but their cellular uptake is often inefficient. Here, the authors show that reversible covalent warhead chemistry improves PROTAC intracellular accumulation and target engagement, and develop a dual inhibitor/degrader of Bruton’s tyrosine kinase
- Wen-Hao Guo
- , Xiaoli Qi
- & Jin Wang
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Article
| Open AccessStructure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions
Small molecule stabilizers of protein–protein interactions hold great therapeutic potential. Based on virtual screening and molecular docking, the authors here develop a strategy to evolve weak, promiscuous inhibitors of 14-3-3 interactions into selective stabilizers of the 14-3-3/ChREBP complex.
- Eline Sijbesma
- , Emira Visser
- & Christian Ottmann
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Article
| Open AccessCyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs
Inhibiting thrombosis without inducing bleeding is a major challenge for anticoagulant agents. Here the authors describe a synthetic FXIIa inhibitor able to efficiently prevent thrombosis in mice and suppress coagulation in artificial lungs in rabbits without increasing the risk of bleeding.
- Jonas Wilbs
- , Xu-Dong Kong
- & Christian Heinis
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Article
| Open AccessStereospecific 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 AccessMode of action of teixobactins in cellular membranes
The natural antibiotic teixobactin kills bacteria by direct binding to their cognate cell wall precursors (Lipid II and III). Here authors use solid-state NMR to reveal the native binding mode of teixobactins and show that teixobactins only weakly bind to Lipid II in anionic cellular membranes.
- Rhythm Shukla
- , João Medeiros-Silva
- & Markus Weingarth
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Article
| Open AccessSelective C-H trifluoromethoxylation of (hetero)arenes as limiting reagent
Selective C-H trifluoromethoxylation of pyridines remains a formidable synthetic challenge. Here, the authors report a silver-mediated late-stage C-H trifluoromethoxylation of arenes and heteroarenes as limiting reagents with trifluoromethoxide anion.
- Zhijie Deng
- , Mingxin Zhao
- & Pingping Tang
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Article
| Open AccessA cysteine selenosulfide redox switch for protein chemical synthesis
Control of cysteine reactivity is of paramount importance for the synthesis of proteins using native chemical ligation. Here, the authors report a readily cleavable N-selenoethyl group attached to cysteine and apply it to the modular assembly of linear and cyclic polypeptides.
- Vincent Diemer
- , Nathalie Ollivier
- & Oleg Melnyk
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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