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  • Drugging histone methyltransferases in cancer
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2020-01-23
    Laia Richart; Raphaël Margueron

    Targeting chromatin-modifying enzymes is a promising strategy for cancer treatment. The antitumor effectivity of compounds inhibiting histone methyltransferases — mainly EZH2 — is currently being tested in phase I/II clinical trials, some of them showing positive results in hematological malignancies and solid tumors of specific mutational background. In this review, we aim at highlighting the recent advances in the field of histone methyltransferase inhibitors and describing the challenges that need to be addressed for their successful implementation in the clinics.

    更新日期:2020-01-23
  • Whole-genome mapping of small-molecule targets for cancer medicine
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2020-01-21
    Stéphanie Solier; Sebastian Müller; Raphaël Rodriguez
    更新日期:2020-01-22
  • Targeted protein degradation: current and future challenges
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2020-01-02
    Alexander Hanzl; Georg E. Winter

    Traditional approaches in the development of small-molecule drugs typically aim to inhibit the biochemical activity of functional protein domains. In contrast, targeted protein degradation aims to reduce overall levels of disease-relevant proteins. Mechanistically, this can be achieved via chemical ligands that induce molecular proximity between an E3 ubiquitin ligase and a protein of interest, leading to ubiquitination and degradation of the protein of interest. This paradigm-shifting pharmacology promises to address several limitations inherent to conventional inhibitor design. Most notably, targeted protein degradation has the potential not only to expand the druggable proteome beyond the reach of traditional competitive inhibitors but also to develop therapeutic strategies of unmatched selectivity. This review briefly summarizes key challenges that remain to be addressed to deliver on these promises and to realize the full therapeutic potential of pharmacologic modulation of protein degradation pathways.

    更新日期:2020-01-02
  • Recent progress in the development of organometallics for the treatment of cancer
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-12-05
    Benjamin S. Murray, Paul J. Dyson

    From their early successes in medicine, organometallic compounds continue to attract interest as potential chemotherapeutics to treat a range of diseases. Here, we show from recent literature selected largely from the last two years that organometallics offer unique opportunities in medicine and, increasingly, a mechanistic-based approach is applied to their development, which has not always been the case.

    更新日期:2019-12-06
  • Metal-based photosensitizers for photodynamic therapy: the future of multimodal oncology?
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-20
    Sherri A. McFarland, Arkady Mandel, Roger Dumoulin-White, Gilles Gasser

    Photodynamic therapy (PDT) is an approved medical technique to treat certain forms of cancer. It has been used to complement traditional anticancer modalities such as surgery, chemotherapy or radiotherapy, and in certain cases, to replace these treatments. One critical parameter of PDT is the photosensitizer (PS); historically, a purely organic macrocyclic tetrapyrrole-based structure. This short review surveys two recent clinical examples of metal complexes, namely TOOKAD®-Soluble and TLD-1433, which have ideal photophysical properties to act as PDT PSs. We highlight the important role played by the metal ions in the PS for PDT activity.

    更新日期:2019-11-20
  • Machine learning for target discovery in drug development
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-14
    Tiago Rodrigues, Gonçalo J.L. Bernardes

    The discovery of macromolecular targets for bioactive agents is currently a bottleneck for the informed design of chemical probes and drug leads. Typically, activity profiling against genetically manipulated cell lines or chemical proteomics is pursued to shed light on their biology and deconvolute drug–target networks. By taking advantage of the ever-growing wealth of publicly available bioactivity data, learning algorithms now provide an attractive means to generate statistically motivated research hypotheses and thereby prioritize biochemical screens. Here, we highlight recent successes in machine intelligence for target identification and discuss challenges and opportunities for drug discovery.

    更新日期:2019-11-14
  • Drugging the gut microbiota: toward rational modulation of bacterial composition in the gut
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-01
    Fernando Altamura, Corinne F. Maurice, Bastien Castagner

    The human gastrointestinal tract hosts almost a trillion microorganisms, organized in a complex community known as the gut microbiota, an integral part of human physiology and metabolism. Indeed, disease-specific alterations in the gut microbiota have been observed in several chronic disorders, including obesity and inflammatory bowel diseases. Correcting these alterations could revert the development of such pathologies or alleviate their symptoms. Recently, the gut microbiota has been the target of drug discovery that goes beyond classic probiotic approaches. This short review examines the promises and limitations of the latest strategies designed to modulate the gut bacterial community, and it explores the druggability of the gut microbiota by focusing on the potential of small molecules and prebiotics.

    更新日期:2019-11-01
  • Targeted and proteome-wide analysis of metabolite-protein interactions.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : null
    Taku Tsukidate,Qiang Li,Howard C Hang

    Understanding the molecular mechanisms of endogenous and environmental metabolites is crucial for basic biology and drug discovery. With the genome, proteome, and metabolome of many organisms being readily available, researchers now have the opportunity to dissect how key metabolites regulate complex cellular pathways in vivo. Nonetheless, characterizing the specific and functional protein targets of key metabolites associated with specific cellular phenotypes remains a major challenge. Innovations in chemical biology are now poised to address this fundamental limitation in physiology and disease. In this review, we highlight recent advances in chemoproteomics for targeted and proteome-wide analysis of metabolite-protein interactions that have enabled the discovery of unpredicted metabolite-protein interactions and facilitated the development of new small molecule therapeutics.

    更新日期:2019-11-01
  • Molecular scaffolds: when DNA becomes the hardware for single-molecule investigations.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-24
    Charlie Gosse,Terence R Strick,Dorota Kostrz

    Over the past few decades, single-molecule manipulation has been widely applied to the real-time analysis of biomolecular interactions. It has enabled researchers to decipher structure-function relationships for polymers, enzymes, and larger-scale molecular machines, in particular by harnessing force to probe both chemical and mechanical stabilities. Nucleic acids have played a central role in this effort because, in addition to their biological significance, they exhibit unique polymeric properties which have recast them as key components participating in numerous experimental designs. In this review, we introduce recent developments highlighting this dual nature of nucleic acids in biophysics, as objects of study but also as tools allowing novel approaches. More specifically, we present molecular scaffolds as an emerging concept and describe their use in single-molecule force spectroscopy. Aspects related to folding and noncovalent interactions will be presented in parallel to research in enzymology, with a focus on the acquisition of thermodynamic and kinetic data.

    更新日期:2019-11-01
  • Modeling catalytic reaction mechanisms in glycoside hydrolases.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-16
    Joan Coines,Lluís Raich,Carme Rovira

    Modeling catalysis in carbohydrate-active enzymes is a daunting challenge because of the high flexibility and diversity of both enzymes and carbohydrates. Glycoside hydrolases (GHs) are an illustrative example, where conformational changes and subtle interactions have been shown to be critical for catalysis. GHs have pivotal roles in industry (e.g. biofuel or detergent production) and biomedicine (e.g. targets for cancer and diabetes), and thus, a huge effort is devoted to unveil their molecular mechanisms. Besides experimental techniques, computational methods have served to provide an in-depth understanding of GH mechanisms, capturing complex reaction coordinates and the conformational itineraries that substrates follow during the whole catalytic pathway, providing a framework that ultimately may assist the engineering of these enzymes and the design of new inhibitors.

    更新日期:2019-11-01
  • Photocrosslinking probes for capture of carbohydrate interactions.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-11
    Han Wu,Jennifer Kohler

    Glycan-mediated interactions are essential in many biological processes and regulate a wide variety of cellular functions. However, characterizing these interactions is difficult because glycan biosynthesis is not template driven and because carbohydrate recognition events are usually of low affinity and transient. Photocrosslinking carbohydrate probes can form a covalent bond with molecules in close proximity on UV irradiation and are capable of capturing interactions between glycans and glycan-binding proteins in situ. Because of these advantages, multiple photocrosslinking carbohydrate probes have been designed and applied to study the biological functions of glycans. This review will discuss recent advances in the development of novel photocrosslinking functional groups and the design of photocrosslinking probes to detect interactions mediated by glycolipids, peptidoglycan, and multivalent carbohydrate ligands. These probes have demonstrated the potential to address some of the major challenges in the study of glycan-mediated interactions in both model systems and in more complex biological settings.

    更新日期:2019-11-01
  • The physical organic chemistry of glycopyranosyl transfer reactions in solution and enzyme-catalyzed.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-07
    Cinzia Colombo,Andrew J Bennet

    Our understanding of the mechanisms of glycopyranosyl transfer that occur in solution, both for the chemical synthesis of complex structures and that for the cleavage of glycosidic bonds has allowed us to design biologically active molecules. Recent efforts on the reactivity of glycopyranosides, which are critical entities in all biological systems, coupled with the advent of modern spectroscopic instrumentation have allowed physical organic chemists to broaden our knowledge of glycosyl transfer reaction transition states, both in solution and for enzyme-catalyzed processes, and of critical high energy intermediates. This review details recent physical organic, kinetic and structural studies that have led to elucidation of several different mechanism for the transfer of glycopyranosyl moieties from various substrates to acceptors, such as water or a sugar hydroxyl group.

    更新日期:2019-11-01
  • Chemically engineered glycan-modified cancer vaccines to mobilize skin dendritic cells.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-05
    Sanne Duinkerken,R Eveline Li,Floortje J van Haften,Tanja D de Gruijl,Fabrizio Chiodo,Sjoerd T T Schetters,Yvette van Kooyk

    Dendritic cell (DC)-targeting vaccines show great promise in increasing antitumor immunity. Glycan-engineered vaccines facilitate both DC targeting and increased uptake by DCs for processing and presentation to CD4+ and CD8+ T cells to induce tumor-specific T-cell responses. However, the complexity of various DC subsets in skin tissues, expressing different glycan-binding receptors that can mediate vaccine uptake or drainage of vaccines via lymphatics directly to the lymph node-resident DCs, complicates the success of vaccines. Moreover, the influx of inflammatory immune cells to the site of vaccination, such as monocytes that differentiate to DCs and coexpress glycan-binding receptors, may contribute to the strength of DC-targeting glycovaccines for future clinical use.

    更新日期:2019-11-01
  • Towards biological applications of nanophotonic tweezers.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-05
    Ryan P Badman,Fan Ye,Michelle D Wang

    Optical trapping (synonymous with optical tweezers) has become a core biophysical technique widely used for interrogating fundamental biological processes on size scales ranging from the single-molecule to the cellular level. Recent advances in nanotechnology have led to the development of 'nanophotonic tweezers,' an exciting new class of 'on-chip' optical traps. Here, we describe how nanophotonic tweezers are making optical trap technology more broadly accessible and bringing unique biosensing and manipulation capabilities to biological applications of optical trapping.

    更新日期:2019-11-01
  • Single-molecule manipulation quantification of site-specific DNA binding.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-05
    Xiaodan Zhao,Shiwen Guo,Chen Lu,Jin Chen,Shimin Le,Hongxia Fu,Jie Yan

    The execution of functions on DNA relies on complex interactions between DNA and proteins in a sequence and structure dependent manner. Accurate quantification of the affinity and kinetics of these interactions is critical for understanding the molecular mechanisms underlying their corresponding biological functions. The development of single-molecule manipulation technologies in the last two decades has made it possible to apply a mechanical constraint to a single DNA molecule and measure the end-to-end extension changes with nanometer resolution in realtime. While it has been shown that such technologies can be used to investigate binding of ligands, which can be proteins or other molecules, to DNA in a fluorescence-label free manner, a systematic review on such applications has been lacking. Here, we provide a review on some of recently developed methods for fluorescence-label free single-molecule quantification of site-specific DNA binding by ligands and demonstrate their wide scope of applications using several examples of binding of ligands to dsDNA and ssDNA binding sites.

    更新日期:2019-11-01
  • Molecular mechanisms regulating O-linked N-acetylglucosamine (O-GlcNAc)-processing enzymes.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-10-28
    Dustin T King,Alexandra Males,Gideon J Davies,David J Vocadlo

    The post-translational modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) dynamically programmes cellular physiology to maintain homoeostasis and tailor biochemical pathways to meet context-dependent cellular needs. Despite diverse roles of played by O-GlcNAc, only two enzymes act antagonistically to govern its cycling; O-GlcNAc transferase installs the monosaccharide on target proteins, and O-GlcNAc hydrolase removes it. The recent literature has exposed a network of mechanisms regulating these two enzymes to choreograph global, and target-specific, O-GlcNAc cycling in response to cellular stress and nutrient availability. Herein, we amalgamate these emerging mechanisms from a structural and molecular perspective to explore how the cell exerts fine control to regulate O-GlcNAcylation of diverse proteins in a selective fashion.

    更新日期:2019-11-01
  • 'Democratized' genomic enzymology web tools for functional assignment.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2018-10-01
    Rémi Zallot,Nils O Oberg,John A Gerlt

    The protein databases contain an exponentially growing number of sequences as a result of the recent increase in ease and decrease in cost of genome sequencing. The rate of data accumulation far exceeds the rate of functional studies, producing an increase in genomic 'dark matter', sequences for which no precise and validated function is defined. Publicly accessible, that is 'democratized,' genomic enzymology web tools are essential to leverage the protein and genome databases for discovery of the in vitro activities and in vivo functions of novel enzymes and proteins belonging to the dark matter. In this review, we discuss the use of web tools that have proven successful for functional assignment. We also describe a mechanism for ensuring the capture of published functional data so that the quality of both curated and automated annotations transfer can be improved.

    更新日期:2019-11-01
  • Advances in synthesis of biotin and assembly of lipoic acid.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2018-09-22
    John E Cronan

    Although biotin and lipoic acid are two universally conserved cofactors essential for intermediary metabolism, their synthetic pathways have become known only in recent years. Both pathways have unusual features. Biotin synthesis in Escherichia coli requires a methylation that is later removed whereas lipoic acid is assembled on the enzymes where it is required for activity by two different pathways.

    更新日期:2019-11-01
  • Glycosphingolipids and lysosomal storage disorders as illustrated by gaucher disease.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-30
    Johannes M F G Aerts,Chi-Lin Kuo,Lindsey T Lelieveld,Daphne E C Boer,Martijn J C van der Lienden,Herman S Overkleeft,Marta Artola

    Glycosphingolipids are important building blocks of the outer leaflet of the cell membrane. They are continuously recycled, involving fragmentation inside lysosomes by glycosidases. Inherited defects in degradation cause lysosomal glycosphingolipid storage disorders. The relatively common glycosphingolipidosis Gaucher disease is highlighted here to discuss new insights in the molecular basis and pathophysiology of glycosphingolipidoses reached by fundamental research increasingly using chemical biology tools. We discuss improvements in the detection of glycosphingolipid metabolites by mass spectrometry and review new developments in laboratory diagnosis and disease monitoring as well as therapeutic interventions.

    更新日期:2019-11-01
  • Using chemical inhibitors to probe AAA protein conformational dynamics and cellular functions.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-03-27
    Jonathan B Steinman,Tarun M Kapoor

    The AAA proteins are a family of enzymes that play key roles in diverse dynamic cellular processes, ranging from proteostasis to directional intracellular transport. Dysregulation of AAA proteins has been linked to several diseases, including cancer, suggesting a possible therapeutic role for inhibitors of these enzymes. In the past decade, new chemical probes have been developed for AAA proteins including p97, dynein, midasin, and ClpC1. In this review, we discuss how these compounds have been used to study the cellular functions and conformational dynamics of AAA proteins. We discuss future directions for inhibitor development and early efforts to utilize AAA protein inhibitors in the clinical setting.

    更新日期:2019-11-01
  • The antimalarial screening landscape-looking beyond the asexual blood stage.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-03-16
    Sabrina Yahiya,Ainoa Rueda-Zubiaurre,Michael J Delves,Matthew J Fuchter,Jake Baum

    In recent years, the research agenda to tackle global morbidity and mortality from malaria disease has shifted towards innovation, in the hope that efforts at the frontiers of scientific research may re-invigorate gains made towards eradication. Discovery of new antimalarial drugs with novel chemotypes or modes of action lie at the heart of these efforts. There is a particular interest in drug candidates that target stages of the malaria parasite lifecycle beyond the symptomatic asexual blood stages. This is especially important given the spectre of emerging drug resistance to all current frontline antimalarials. One approach gaining increased interest is the potential of designing novel drugs that target parasite passage from infected individual to feeding mosquito and back again. Action of such therapeutics is geared much more at the population level rather than just concerned with the infected individual. The search for novel drugs active against these stages has been helped by improvements to in vitro culture of transmission and pre-erythrocytic parasite lifecycle stages, robotic automation and high content imaging, methodologies that permit the high-throughput screening (HTS) of compound libraries for drug discovery. Here, we review recent advances in the antimalarial screening landscape, focussed on transmission blocking as a key aim for drug-treatment campaigns of the future.

    更新日期:2019-11-01
  • Editorial overview: From the iceman to modern medicine.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-06-11
    Yimon Aye,Paul J Hergenrother

    更新日期:2019-11-01
  • New players in phototherapy: photopharmacology and bio-integrated optoelectronics.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-05-21
    Johannes Morstein,Dirk Trauner

    Photodynamic therapy and phototherapy are used in the clinic to treat dermatological conditions, cancer, macular degeneration, and a variety of other diseases. Despite their long history and widespread application, the scope of these therapeutic approaches has been limited by a lack of specificity and challenges with light delivery. In recent years, much progress has been made in these regards. Photopharmacology has provided drug-like molecules that change their efficacy upon irradiation and allow for the optical control of a wide range of defined biological targets. Many photopharmaceuticals are now used in vivo and some show promising results in preclinical development. At the same time, new bioelectronics for subdermal light delivery have been engineered that could enable phototherapy deep in tissue, for example within the human brain. These developments could increase the impact of photodynamic therapy in human precision medicine.

    更新日期:2019-11-01
  • Natural products as chemical tools to dissect complex biology in C. elegans.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-05-19
    Rebecca A Butcher

    The search for novel pheromones, hormones, and other types of natural products in the nematode Caenorhabditis elegans has accelerated over the last 10-15 years. Many of these natural products perturb fundamental processes such as developmental progression, metabolism, reproductive and somatic aging, and various behaviors and have thus become essential tools for probing these processes, which are difficult to study in higher organisms. Furthermore, given the similarity between C. elegans and parasitic nematodes, these natural products could potentially be used to manipulate the development and behavior of parasitic nematodes and target the infections caused by them.

    更新日期:2019-11-01
  • Genetically encoded fragment-based discovery.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-05-06
    Ratmir Derda,Simon Ng

    This opinion describes recent advances of molecular discovery technology dubbed Genetically Encoded Fragment-Based Discovery (GE-FBD). GE-FBD starts from a known ligand or 'fragment' that binds to a desired target weakly and often with low specificity. Covalent incorporation of fragment into a diverse, genetically encoded library of peptides yields a library of peptide-fragment combinations. Selection from such a library has a high likelihood to identify ligands, in which the peptides bind to distinct adjacent pockets of the target in synergy with the fragment and exhibits enhanced affinity and specificity when compared to the fragment itself. GE-FBD could employ fragments that bind non-covalently as well as reversible covalent warheads. The key advances in GE-FBD include (i) synthetic chemistry that enables incorporation of diverse fragments into both linear and cyclic peptide libraries; (ii) quantification of multi-step modifications in million-to-billion library members, (iii) and chemical transformations that permit incorporation of fragments with concurrent topological change from linear to macrocyclic topologies.

    更新日期:2019-11-01
  • Pharmacokinetic-pharmacodynamic models that incorporate drug-target binding kinetics.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-04-29
    Fereidoon Daryaee,Peter J Tonge

    Pharmacokinetic/pharmacodynamic (PK/PD) models predict the effect time course resulting from a drug dose. In this review, we summarize the development of mechanistic PK/PD models that explicitly integrate the kinetics of drug-target interactions into predictions of drug activity. Such mechanistic models are expected to have several advantages over approaches in which concentration and effect are linked using variations of the Hill equation, and where preclinical data are often used as a starting point for modeling drug activity. Instead, explicit use of the full kinetic scheme for drug binding enables time-dependent changes in target occupancy to be calculated using the kinetics of drug-target interactions and drug PK, providing a more precise picture of target engagement and drug action in the non-equilibrium environment of the human body. The mechanistic PK/PD models also generate target vulnerability functions that link target occupancy and effect, and inform on the sensitivity of a target to engagement by a drug. Key factors such as the rate of target turnover can also be integrated into the modeling which, together with target vulnerability, provide additional information on the PK profile required to achieve the desired pharmacological effect and on the utility of kinetic selectivity in developing drugs for specific targets.

    更新日期:2019-11-01
  • Targeting defective proteostasis in the collagenopathies.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-04-28
    Madeline Y Wong,Matthew D Shoulders

    The collagenopathies are a diverse group of diseases caused primarily by mutations in collagen genes. The resulting disruptions in collagen biogenesis can impair development, cause cellular dysfunction, and severely impact connective tissues. Most existing treatment options only address patient symptoms. Yet, while the disease-causing genes and proteins themselves are difficult to target, increasing evidence suggests that resculpting the intracellular proteostasis network, meaning the machineries responsible for producing and ensuring the integrity of collagen, could provide substantial benefit. We present a proteostasis-focused perspective on the collagenopathies, emphasizing progress toward understanding how mechanisms of collagen proteostasis are disrupted in disease. In parallel, we highlight recent advances in small molecule approaches to tune endoplasmic reticulum proteostasis that may prove useful in these disorders.

    更新日期:2019-11-01
  • Targeted protein degradation: elements of PROTAC design.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-04-21
    Stacey-Lynn Paiva,Craig M Crews

    Targeted protein degradation using Proteolysis Targeting Chimeras (PROTACs) has emerged as a novel therapeutic modality in drug discovery. PROTACs mediate the degradation of select proteins of interest (POIs) by hijacking the activity of E3 ubiquitin ligases for POI ubiquitination and subsequent degradation by the 26S proteasome. This hijacking mechanism has been used to degrade various types of disease-relevant POIs. In this review, we aim to highlight the recent advances in targeted protein degradation and describe the challenges that need to be addressed in order to efficiently develop potent PROTACs.

    更新日期:2019-11-01
  • Will morphing boron-based inhibitors beat the β-lactamases?
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-04-21
    Alen Krajnc,Pauline A Lang,Tharindi D Panduwawala,Jürgen Brem,Christopher J Schofield

    The β-lactams remain the most important antibacterials, but their use is increasingly compromised by resistance, importantly by β-lactamases. Although β-lactam and non-β-lactam inhibitors forming stable acyl-enzyme complexes with nucleophilic serine β-lactamases (SBLs) are widely used, these are increasingly susceptible to evolved SBLs and do not inhibit metallo-β-lactamases (MBLs). Boronic acids and boronate esters, especially cyclic ones, can potently inhibit both SBLs and MBLs. Vaborbactam, a monocyclic boronate, is approved for clinical use, but its β-lactamase coverage is limited. Bicyclic boronates rapidly react with SBLs and MBLs forming stable enzyme-inhibitor complexes that mimic the common anionic high-energy tetrahedral intermediates in SBL/MBL catalysis, as revealed by crystallography. The ability of boronic acids to 'morph' between sp2 and sp3 hybridisation states may help enable potent inhibition. There is limited structure-activity relationship information on the (bi)cyclic boronate inhibitors compared to β-lactams, hence scope for creativity towards new boron-based β-lactamase inhibitors/antibacterials.

    更新日期:2019-11-01
  • Histone deacetylases as an epigenetic pillar for the development of hybrid inhibitors in cancer.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-04-16
    Giulia Stazi,Rossella Fioravanti,Antonello Mai,Andrea Mattevi,Sergio Valente

    The polypharmacology strategy of multi-targeting drugs acting on different biological pathways is capturing the researchers' attention, particularly in cancer. The simultaneous inhibition of two or more targets by drug combination or by a single 'hybrid molecule' can provide improved therapeutic efficacy when compared to the one-target inhibitors. In this regard, because of their multiple anticancer effects, histone deacetylase inhibitors have become a privileged tool for the development of hybrid drugs. The clinical trials of two multi-acting chimeras, HDAC/EGFR/HER2 and HDAC/PI3K inhibitors, encouraged the design of novel hybrids, such as compounds 22a (LSD1/HDAC) and 16a (CDK4/JAK1/HDAC), which showed superior anticancer effects than single-targeting agents or their combination both in cellular and mouse models.

    更新日期:2019-11-01
  • Recent advances in the development of HBV capsid assembly modulators.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-04-06
    Bhavitavya Nijampatnam,Dennis C Liotta

    Hepatitis B virus (HBV) infections represent a significant burden on global public health. Current HBV treatments using nucleos(t)ide analogs (NAs) and PEG interferons cannot fully alleviate this burden as they do not affect the transcriptional activity of the tenacious covalently closed circular DNA (cccDNA) responsible for viral persistence. Capsid assembly modulators (CAMs) disrupt the encapsidation of pre-genomic RNA and can cause nucleocapsid disassembly, thereby affecting multiple steps of HBV replication and reduction of cccDNA pools. This review provides a concise overview of the development of CAMs and the progress achieved in understanding their interactions with HBV core proteins.

    更新日期:2019-11-01
  • Label-free target identification in drug discovery via phenotypic screening.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-04-02
    Hankum Park,Jaeyoung Ha,Seung Bum Park

    Phenotypic screening has demonstrated its advantage in the discovery of first-in-class therapeutics, whereas target-based screening has showed strength for follower drugs. Owing to the unbiased nature of phenotypic screening, novel druggable proteins can be uncovered by target identification. Chemical label-free target identification methods can eliminate the functionalization step of an original bioactive compound. Herein, we summarize recent advances in the development of label-free target identification methods, which are based on changes in protein stability against proteolysis, and chemical and thermal denaturation. Owing to the increasing application of shift in thermal stability for protein analysis in live cells and tissues, we mainly focus on the cellular stability shift assay and its proteome-wide application for target identification.

    更新日期:2019-11-01
  • Developing zebrafish disease models for in vivo small molecule screens.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-04-01
    Pui-Ying Lam,Randall T Peterson

    The zebrafish is a model organism that allows in vivo studies to be performed at a scale usually restricted to in vitro studies. As such, the zebrafish is well suited to in vivo screens, in which thousands of small molecules are tested for their ability to modify disease phenotypes in zebrafish disease models. Numerous approaches have been developed for modeling human diseases in zebrafish, including mutagenesis, transgenesis, pharmacological approaches, wounding, and exposure to infectious or cancerous agents. We review the various strategies for modeling human diseases in zebrafish and discuss important considerations when developing zebrafish models for use in in vivo small molecule screens.

    更新日期:2019-11-01
  • Modulating protein-protein interaction networks in protein homeostasis.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-03-27
    Mengqi Zhong,Gregory M Lee,Eline Sijbesma,Christian Ottmann,Michelle R Arkin

    Protein-protein interactions (PPIs) occur in complex networks. These networks are highly dependent on cellular context and can be extensively altered in disease states such as cancer and viral infection. In recent years, there has been significant progress in developing inhibitors that target individual PPIs either orthosterically (at the interface) or allosterically. These molecules can now be used as tools to dissect PPI networks. Here, we review recent examples that highlight the use of small molecules and engineered proteins to probe PPIs within the complex networks that regulate protein homeostasis. Researchers have discovered multiple mechanisms to modulate PPIs involved in host/viral interactions, deubiquitinases, the ATPase p97/VCP, and HSP70 chaperones. However, few studies have evaluated the effect of such modulators on the target's network or have compared the biological implications of different modulation strategies. Such studies will have an important impact on next generation therapeutics.

    更新日期:2019-11-01
  • Reactive-cysteine profiling for drug discovery.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-03-22
    Aaron J Maurais,Eranthie Weerapana

    The recognition that only a small percentage of known human gene products are druggable using traditional modes of non-covalent ligand design, has led to a resurgence in targeted covalent inhibitors. Covalent inhibitors offer advantages over non-covalent inhibitors in engaging otherwise challenging targets. Reactive cysteine residues on proteins are a common target for covalent inhibitors, whereby the high nucleophilicity of the cysteine thiol under physiological conditions provides an ideal anchoring site for electrophilic small molecules. A chemical-proteomic platform, termed isoTOP-ABPP, allows for profiling cysteine reactivity in complex proteomes and is one of many techniques that can aid in two aspects of the covalent-inhibitor development process: (1) to identify functional cysteines that lead to modulation of protein activity through covalent modification; and, (2) to determine cellular targets and evaluate promiscuity of electrophilic fragments, small molecules, and natural products. Herein, we discuss recent advances in isoTOP-ABPP and potential applications of this technology in the drug-discovery pipeline.

    更新日期:2019-11-01
  • Sphingolipids and membrane targets for therapeutics.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-03-22
    Robbie Loewith,Howard Riezman,Nicolas Winssinger

    Lipids and membranes are often strongly altered in various diseases and pathologies, but are not often targeted for therapeutic advantage. In particular, the sphingolipids are particularly sensitive to altered physiology and have been implicated as important players in not only several rare hereditary diseases, but also other major pathologies, including cancer. This review discusses some potential targets in the sphingolipid pathway and describes how the initial drug compounds have been evolved to create potentially improved therapeutics. This reveals how lipids and their interactions with proteins can be used for therapeutic advantage. We also discuss the possibility that modification of the physical properties of membranes could also affect intracellular signaling and be of therapeutic interest.

    更新日期:2019-11-01
  • Construction of ligand assay systems by protein-based semisynthetic biosensors.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-03-16
    Seiji Sakamoto,Shigeki Kiyonaka,Itaru Hamachi

    Proteins as causative agents of diseases such as cancers, diabetes and neurological disorders are attractive drug targets. For developing chemicals selectively acting on key disease-causing proteins, one useful concept is the direct conversion of such target proteins into biosensors. This approach provides ligand-binding assay systems based on protein-based biosensors, which can quantitatively evaluate interactions between the protein and a specific ligand in many environments. Site-specific chemical modifications are used widely for the creation of protein-based semisynthetic biosensors in vitro. Notably, a few bio-orthogonal approaches capable of selectively modifying drug-targets have been developed, allowing conversion of specific target proteins into semisynthetic biosensors in live cells. These biosensors can be used for quantitative drug binding analyses in native environments. In this review, we discuss recent efforts for the construction of ligand assay systems using semisynthetic protein-based biosensors and their application to quantitative analysis and high-throughput screening of small molecules for drug discovery.

    更新日期:2019-11-01
  • The more the merrier: how homo-oligomerization alters the interactome and function of ribonucleotide reductase.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-18
    Marcus J C Long,Alexandra Van Hall-Beauvais,Yimon Aye

    Stereotyped as a nexus of dNTP synthesis, the dual-subunit enzyme - ribonucleotide reductase (RNR) - is coming into view as a paradigm of oligomerization and moonlighting behavior. In the present issue of 'omics', we discuss what makes the larger subunit of this enzyme (RNR-α) so interesting, highlighting its emerging cellular interactome based on its unique oligomeric dynamism that dictates its compartment-specific occupations. Linking the history of the field with the multivariable nature of this exceedingly sophisticated enzyme, we further discuss implications of new data pertaining to DNA-damage response, S-phase checkpoints, and ultimately tumor suppression. We hereby hope to provide ideas for those interested in these fields and exemplify conceptual frameworks and tools that are useful to study RNR's broader roles in biology.

    更新日期:2019-11-01
  • Imaging dynamic cell signaling in vivo with new classes of fluorescent reporters.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2019-11-05
    Xiaokun Shu

    Dynamical features of cell signaling are the essence of living organisms. To understand animal development, it is fundamental to investigate signaling dynamics in vivo. Robust reporters are required to visualize spatial and temporal dynamics of enzyme activities and protein-protein interactions involved in signaling pathways. In this review, we summarize recent development in the design of new classes of fluorescent reporters for imaging dynamic activities of proteases, kinases, and protein-protein interactions. These reporters operate on new physical and/or chemical principles; achieve large dynamic range, high brightness, and fast kinetics; and reveal spatiotemporal dynamics of signaling that is correlated with developmental events such as embryonic morphogenesis in live animals including Drosophila and zebrafish. Therefore, many of these reporters are great tools for biological discovery and mechanistic understanding of animal development and disease progression.

    更新日期:2019-11-01
  • Synthetic carbohydrate antigens for HIV vaccine design.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2014-01-28
    Lai-Xi Wang

    The heavy glycosylation of HIV envelope constitutes a strong defense mechanism for the virus to evade host immune response, which accounts for a major barrier for HIV vaccine development. Nevertheless, the identification of a number of glycan-dependent broadly HIV-neutralizing antibodies from HIV-infected individuals, including 2G12, PG9, PG16, PGT121-123, PGT125-128, and PGT135, strongly suggests that the defensive viral 'glycan shield' can be important targets of vaccines. The novel glycan recognition mode exhibited by these antibodies provides new templates for immunogen design. This review highlights recent work on the characterization of the glycan-dependent epitopes of these neutralizing antibodies and recent advances in the synthesis of the relevant carbohydrate antigens for HIV vaccine design.

    更新日期:2019-11-01
  • Context and complexity: the next big thing in synthetic glycobiology.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2014-01-28
    Todd L Lowary

    Complex glycans participate in many essential life processes. Studies of glycan-mediated biological events have traditionally employed structurally defined fragments of the more elaborate natural molecules. However, it is now clear that this approach may sometimes be insufficient and this realization has prompted a desire to synthesize glycans of similar size and complexity to those found in nature. We highlight here recent work describing the synthesis of such molecules.

    更新日期:2019-11-01
  • Structural investigation of multivalent carbohydrate-protein interactions using synthetic biomolecules.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2014-01-28
    Valentin Wittmann

    Understanding multivalent carbohydrate-protein interactions at the molecular level requires access to structural details of these important biological recognition processes. Recent developments toward this goal comprise the use of conformationally defined molecular rulers in combination with binding assays, crystallographic investigation of complexes of multivalent ligands and their target proteins, and distance measurements in the nanometer range by EPR spectroscopy.

    更新日期:2019-11-01
  • Membrane proteins by accident or design.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2014-01-28
    John Simms,Paula J Booth

    Protein design is a valuable tool to create bespoke proteins with desired properties as well as for investigating sequence, structure and function relationships. Membrane protein design is a burgeoning field that is hampered by the lack of high-resolution structural information. In spite of these shortcomings, computational methods have offered a route towards blueprints for these hydrophobic proteins. Advances in structural scoring and sampling methods are enabling more accurate predictions of a folded structure from the primary amino acid sequence. This review highlights a number of novel studies focusing on the methods and information used to successfully design membrane proteins.

    更新日期:2019-11-01
  • Constructing arrays of proteins.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2014-01-28
    John C Sinclair

    The construction of crystalline arrays allows proteins to be presented in a dense, oriented and functional way that also facilitates determination of their structure. Rational design of these supramolecular structures is becoming increasingly tractable with recent successes exploiting both innate protein symmetry and advances in protein–protein interface design. Pre-existing symmetry minimizes the number of non-native interfaces that must be produced, and the use of symmetric interfaces facilitates protein alignment. Arrays in which metal coordination or peptide binding are responsible for the inter-particle associations show particular promise due to the malleable and reversible nature of these interactions. Cross-pollination of the principles that underlie successful strategies is likely to produce rapid advances in this field and consequent benefits to both nanotechnology and structural biology.

    更新日期:2019-11-01
  • Computational protein design of ligand binding and catalysis.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2014-01-28
    Kaspar Feldmeier,Birte Höcker

    The vision of custom-made proteins by computation appears closer than ever. Computational methods have advanced rapidly in recent years and proteins have been designed to catalyze new reactions. A number of second-generation enzyme designs analyzed possible bottlenecks and started tackling emergent problems. Detailed experimental analysis combined with structure determination and molecular dynamics simulations as well as design optimization with directed evolution techniques have led to important insights. While ligand recognition seems to be particularly problematic, new approaches focus on this design aspect and promising improvements have been made.

    更新日期:2019-11-01
  • Synthetic mammalian gene circuits for biomedical applications.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2014-01-28
    Haifeng Ye,Dominique Aubel,Martin Fussenegger

    Synthetic biology is the science of reassembling cataloged and standardized biological items in a systematic and rational manner to create and engineer functional biological designer devices, systems and organisms with novel and useful, preferably therapeutic functions. Synthetic biology has significantly advanced the design of complex genetic networks that can reprogram metabolic activities in mammalian cells and provide novel therapeutic strategies for future gene-based and cell-based therapies. Synthetic biology-inspired therapeutic strategies provide new opportunities for improving human health in the 21st century. This review covers the most recent synthetic mammalian circuits designed for therapy of diseases such as metabolic disorders, cancer, and immune disorders. We conclude by discussing current challenges and future perspectives for biomedical applications of synthetic mammalian gene networks.

    更新日期:2019-11-01
  • Olefin metathesis in glycobiology: new routes towards diverse neoglycoconjugates.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Michiel A Leeuwenburgh,Gijsbert A van der Marel,Herman S Overkleeft

    This report provides a historical overview of the implementation of olefin metathesis in carbohydrate chemistry, with the emphasis on the construction of neoglycoconjugates. The current state-of-the-art in catalyst design allows the preparation of carbohydrate-containing molecules with great structural and functional diversity. Recent examples of complex neoglycoconjugates, including glycopolymers, glycoclusters, glycopeptide and glycolipid analogues are highlighted. Finally, future perspectives in the scope of olefin metathesis mediated neoglycoconjugate synthesis are discussed.

    更新日期:2019-11-01
  • Synthesis and conformational analysis of arabinofuranosides, galactofuranosides and fructofuranosides.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Todd L Lowary

    Many microorganisms produce biologically important polysaccharides containing galactofuranosyl, arabinofuranosyl and/or fructofuranosyl residues. Recent interest in identifying antibiotics that act by inhibiting the biosynthesis of these glycans has resulted in the development of new and efficient methods for the assembly of oligosaccharides containing furanose residues. In general, it is now possible to synthesize any furanose-containing oligosaccharide with reasonable efficiency. In conjunction with these synthetic investigations, an increasing number of studies have probed the conformation of furanose rings, and a solid appreciation of the conformational preferences of key furanoside ring systems is now available.

    更新日期:2019-11-01
  • Hydrophilic to amphiphilic design in redox protein maquettes.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Bohdana M Discher,Ronald L Koder,Christopher C Moser,P Leslie Dutton

    De novo protein design has created small, robust protein-cofactor complexes that serve as simplified working models, or maquettes, for the much more complicated natural oxidoreductases. We review the research avenues that spring from the better characterized water-soluble hydrophilic maquettes and guide the construction of amphiphilic maquettes patterned on membrane-bound oxidoreductases that couple electron transfer to transmembrane proton-motive force. We address the special working challenges and opportunities that arise with amphiphilic maquettes designed to assemble in membranes, along with the redox and pigment cofactors required to promote light activated electron transfer, redox-coupled electric field generation, proton exchange and transmembrane charge motion.

    更新日期:2019-11-01
  • Synthetic developments towards PNA-peptide conjugates.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Martijn C de Koning,Gijs A van der Marel,Mark Overhand

    Since the discovery of peptide nucleic acids (PNAs) as DNA mimics in the early 1990s, a tremendous effort has been directed to their application as antisense and antigene probes. With the aim of further enhancing their properties, PNAs have been conjugated to a variety of effector molecules. Among these, small peptide fragments, often derived from functional proteins, are able to convey their specific properties to the conjugate.

    更新日期:2019-11-01
  • Beyond A, C, G and T: augmenting nature's alphabet.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Allison A Henry,Floyd E Romesberg

    Efforts to expand the genetic alphabet are predicated upon a stable and replicable third base pair. Recent progress has resulted in the development of several candidates that are both stable in duplex DNA and replicated by DNA polymerases with various degrees of efficiency and fidelity. The candidate base pairs draw upon unnatural hydrogen-bonding topologies as well as upon shape complementarity and hydrophobic forces. This review provides a critical comparison of the third base pair candidates and discusses the further work required to expand the genetic alphabet.

    更新日期:2019-11-01
  • Recent improvements in antigene technology.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Sabrina Buchini,Christian J Leumann

    DNA triple-helix-based approaches to control and modulate cellular functions on the level of genomic DNA (antigene technology) suffered in the past from a stepmother-like treatment in comparison to the flourishing field of oligonucleotide-based control of translation (antisense technology). This was mostly due to lack of affinity of triplex-forming oligonucleotides to their DNA target, to sequence restriction constraints imposed by the triple helical recognition motifs and by open questions to the accessibility of the target DNA. Recent developments in the area have brought about new bases that specifically recognize pyrimidine-purine inversion sites as well as sugar modifications, for example, the 2'-aminoethoxy-oligonucleotides or oligonucleotides based on the locked nucleic acid sugar unit, which greatly enhance triplex stability and alleviate in part the sequence restriction constraints. With this, sequence-specific genomic DNA manipulation is starting to become a useful tool in biotechnology.

    更新日期:2019-11-01
  • Modeling ion channel regulation.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    G Andrew Woolley,Tyler Lougheed

    Remarkable recent successes in structure determinations of voltage-gated channels, ligand-gated channels, mechanosensitive channels and proton channels have advanced our understanding of the molecular basis of ion channel gating substantially. Models have helped to clarify aspects of this process and are now being designed as sophisticated biomimetics for various technological applications.

    更新日期:2019-11-01
  • Self-assembly in mesoscopic dimension and artificial supramolecular membranes.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Nobuo Kimizuka

    The development of mesoscopic supramolecular architectures is an area of growing interest. The field has grown from early works on bilayer membranes, and the design of large (super- or giant-) amphiphiles, hybrid amphiphiles and supramolecular membranes have now been described. Impartment of amphiphilicity to a unit supermolecule allows their hierarchical self-assembly to the mesoscopic structures. A supramolecular combinatorial approach is useful in the development of functional self-assemblies. In addition, self-assembly in ionic liquids has been introduced as a promising area in materials chemistry.

    更新日期:2019-11-01
  • Evolutionary markers in the (beta/alpha)8-barrel fold.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    M Cristina Vega,Esben Lorentzen,Anni Linden,Matthias Wilmanns

    Enzymes with the (beta/alpha)(8)-barrel fold are involved in the catalysis of a wide variety of biochemical reactions. The active sites of these enzymes are located on the C-terminal face of the central beta-barrel. Conserved amino acid sequence, as well as secondary, tertiary and quaternary structure patterns are providing a rich body of data to support the premise of a common ancestry of many members of the (beta/alpha)(8)-barrel fold family of enzymes. Recent data indicate that there is at least one example of a bienzyme that functions as an ammonia channel, adding a new level of functional diversity to the (beta/alpha)(8)-barrel fold. These proteins have become ideal tools that can be used in conjunction with directed evolution techniques to engineer novel catalytic activities.

    更新日期:2019-11-01
  • Imitating the humoral immune response.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Arne Skerra

    The immune system makes use of two distinct mechanisms to mount an efficient response against almost every foreign macromolecular substance. First, antibodies with their robust immunoglobulin domain architecture provide a rigid scaffold to support six hypervariable loops, capable of forming highly diverse binding sites. Second, an efficient genetic mechanism has evolved to create sequence diversity at the somatic level in a step-wise process, whereby random recombination of an inherited set of gene segments is followed by hypermutation events. Insight into the corresponding molecular mechanisms is developing rapidly and enables adaptation of the emerging principles to the creation of artificial binding proteins in vitro, using the techniques of combinatorial biotechnology. Thus, novel types of receptor molecules have been constructed from alternative scaffolds, including alpha-helical bundle and beta-barrel proteins. These may provide superior tools for the recognition, targeting or separation of a wide range of biomolecular structures or substances in biological research, technology, and even medicine.

    更新日期:2019-11-01
  • Functional models for mononuclear nonheme iron enzymes.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Jan-Uwe Rohde,Michael R Bukowski,Lawrence Que

    Increasing interest in mononuclear nonheme iron enzymes that activate dioxygen has resulted in an explosion of information on such enzymes in recent years. Concomitantly, efforts to model the active sites of these enzymes have produced synthetic complexes capable of mimicking some aspect of the reactivity of the metal center in several enzymes. These functional models carry out oxidative transformations analogous to those catalyzed by the enzymes and in some cases allow iron(III)-peroxo or iron(IV)-oxo intermediates to be trapped and characterized.

    更新日期:2019-11-01
  • Towards artificial photosynthesis: ruthenium-manganese chemistry mimicking photosystem II reactions.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Leif Hammarström

    The reaction center Photosystem II is a key component of the most successful solar energy converting machinery on earth: the oxygenic photosynthesis. Photosystem II uses light to drive the reduction of plastoquinone and the oxidation of water. Water-oxidation is catalyzed by a manganese cluster and gives the organism an abundant source of electrons. The principles of photosynthesis have inspired chemists to mimic these reactions in artificial molecular assemblies. Synthetic light-harvesting antennae and light-induced charge separation systems have been demonstrated by several groups. More recently, there has been an increasing effort to mimic Photosystem II by coupling light-driven charge separation to water oxidation, catalyzed by synthetic manganese complexes.

    更新日期:2019-11-01
  • Light-harvesting dendrimers.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-12-04
    Vincenzo Balzani,Paola Ceroni,Mauro Maestri,Veronica Vicinelli

    Dendrimers are well-defined, tree-like macromolecules, with a high degree of order and the possibility to contain selected chemical units in predetermined sites of their structure. Dendrimers are currently attracting the interest of many scientists because of their unusual chemical and physical properties and the wide range of potential applications. It is possible to design and synthesize dendrimers containing a variety of chromophoric groups organized in the dimensions of time, energy and space so as to obtain efficient light-harvesting devices that can be useful for solar energy conversion and other purposes.

    更新日期:2019-11-01
  • Metabonomics: NMR spectroscopy and pattern recognition analysis of body fluids and tissues for characterisation of xenobiotic toxicity and disease diagnosis.
    Curr. Opin. Chem. Biol. (IF 8.544) Pub Date : 2003-10-29
    Julian L Griffin

    Global profiling tools are required to fully understand the impact of genetic modifications and toxicological interventions on the network of transcripts, proteins and metabolites found within a cell, tissue or organism. High-resolution 1H NMR spectroscopy in conjunction with statistical pattern recognition is one such technique, referred to as metabonomics or metabolomics, which is increasingly being used to globally profile metabolites. This review examines analytical advances in NMR spectroscopy that have aided this development including high-resolution magic angle spinning NMR spectroscopy, cryogenically cooled probes and high-through put systems. This has allowed the approach to identify genetically modified yeast strains and distinguish both disease presence and severity in coronary heart disease.

    更新日期:2019-11-01
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