Editorial overview: Recent advance in chemical genetics and chemical epigenetics.
PMID: 31377107 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - July 31, 2019 Category: Biochemistry Authors: Lei X, Li XD Tags: Curr Opin Chem Biol Source Type: research

Recent developments in spontaneous Raman imaging of living biological cells.
Abstract Raman spectroscopy is a non-invasive optical technique for measuring chemical information from samples including biological cells. With its high sensitivity and compatibility with in vitro samples, Raman spectroscopy is increasing in popularity as a tool for acquiring chemical images of cellular samples in fields including parasitology, pharmacology, and oncology. This review describes emerging technologies that are improving the speed, resolution, and impact of Raman imaging techniques. Topics include novel instrumentation for data acquisition and improvements on techniques for displaying hyperspectral d...
Source: Current Opinion in Chemical Biology - July 22, 2019 Category: Biochemistry Authors: Durrant B, Trappett M, Shipp D, Notingher I Tags: Curr Opin Chem Biol Source Type: research

Towards functional de novo designed proteins.
Abstract Our ability to design completely de novo proteins is improving rapidly. This is true of all three main approaches to de novo protein design, which we define as: minimal, rational and computational design. Together, these have delivered a variety of protein scaffolds characterised to high resolution. This is truly impressive and a major advance from where the field was a decade or so ago. That all said, significant challenges in the field remain. Chief amongst these is the need to deliver functional de novo proteins. Such designs might include selective and/or tight binding of specified small molecules, or...
Source: Current Opinion in Chemical Biology - July 20, 2019 Category: Biochemistry Authors: Dawson WM, Rhys GG, Woolfson DN Tags: Curr Opin Chem Biol Source Type: research

Can single molecule localization microscopy detect nanoclusters in T cells?
Abstract Nanoclusters of cell surface receptors have been detected with single molecule localization microscopy (SMLM) and are thought to mediate signal transduction. Clustering of the T cell receptor (TCR), for example, was reported to control signalling efficiency and antigen discrimination. However, the ability to detect nanoclusters with SMLM has been questioned. Here, we review the detection limits of SMLM as defined by both the physical limits and data processing, as well as evidence for nanoclusters arising from complementary techniques. We conclude with an outlook of how future data analysis can reveal the...
Source: Current Opinion in Chemical Biology - July 17, 2019 Category: Biochemistry Authors: Feher K, Halstead JM, Goyette J, Gaus K Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Advances and future prospects of molecular imaging for studying and quantifying biological processes.
PMID: 31311706 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - July 13, 2019 Category: Biochemistry Authors: Kukura P, Myong S Tags: Curr Opin Chem Biol Source Type: research

Nucleic acid enzymes based on functionalized nucleosides.
Abstract Nucleic acid-based enzymes have recently joined their proteinaceous counterparts as important biocatalysts. While RNA enzymes (ribozymes) are found in nature, deoxyribozymes or DNAzymes are man-made entities. Numerous ribozymes and DNAzymes have been identified by Darwinian selection methods to catalyze a broad array of chemical transformations. Despite these important advances, practical applications involving nucleic acid enzymes are often plagued by relatively poor pharmacokinetic properties and cellular uptake, rapid degradation by nucleases and/or by the limited chemical arsenal carried by natural DN...
Source: Current Opinion in Chemical Biology - July 12, 2019 Category: Biochemistry Authors: Hollenstein M Tags: Curr Opin Chem Biol Source Type: research

New discoveries in bacterial N-glycosylation to expand the synthetic biology toolbox.
Abstract Historically, protein glycosylation was believed to be restricted to eukaryotes, but now is abundantly represented in all three domains of life. The first bacterial N-linked glycosylation system was discovered in the Gram-negative pathogen, Campylobacter jejuni, and subsequently transferred into the heterologous Escherichia coli host beginning a new era of synthetic bacterial glycoengineering. Since then, additional N-glycosylation pathways have been characterized resembling the classical C. jejuni system and unconventional new approaches for N-glycosylation have been uncovered. These include cytoplasmic ...
Source: Current Opinion in Chemical Biology - July 6, 2019 Category: Biochemistry Authors: Nothaft H, Szymanski CM Tags: Curr Opin Chem Biol Source Type: research

Visualizing transcription: key to understanding gene expression dynamics.
Abstract Visualization of transcription in living cells has taught us that genes are often transcribed in bursts, with periods of gene activity interspersed by periods of inactivity. Recently, technological advances in live-cell imaging have provided a more detailed picture of the characteristics of transcriptional bursts, and have allowed direct visualization of the upstream regulatory steps of bursting at single-molecule resolution. In this review, we highlight the latest insights into transcription dynamics and we discuss recent developments in understanding the regulation of transcriptional bursting through th...
Source: Current Opinion in Chemical Biology - July 5, 2019 Category: Biochemistry Authors: Brouwer I, Lenstra TL Tags: Curr Opin Chem Biol Source Type: research

The role of bacterial lipid diversity and membrane properties in modulating antimicrobial peptide activity and drug resistance.
We describe the current models of membrane disruption caused by AMPs and the changes in the structural properties that microbial membranes undergo in response to AMPs. This is followed by an outline of how the phospholipid composition of microbial membranes contributes to the changes in membrane bilayer structure and how the composition can be analysed in significant detail by modern lipidomic techniques. Finally, we discuss the challenges to fully analyse microbial membrane composition and structure that may occur during the development of resistance to AMPs. PMID: 31260926 [PubMed - as supplied by publisher] (Source...
Source: Current Opinion in Chemical Biology - June 28, 2019 Category: Biochemistry Authors: Lee TH, Hofferek V, Separovic F, Reid GE, Aguilar MI Tags: Curr Opin Chem Biol Source Type: research

High-speed atomic force microscopy.
Abstract High-speed atomic force microscopy (HS-AFM) is a unique tool for molecular imaging. It can directly visualize protein molecules during their functional activity at high spatiotemporal resolution, without a marker being attached to the molecules. Molecular dynamics filmed with HS-AFM can provide mechanistic insights into the functional molecular processes that are hard to be attained with other approaches. In this mini review, I highlight some of recent relevant studies of proteins by HS-AFM imaging after brief descriptions of AFM and HS-AFM. PMID: 31254806 [PubMed - as supplied by publisher] (Source:...
Source: Current Opinion in Chemical Biology - June 26, 2019 Category: Biochemistry Authors: Ando T Tags: Curr Opin Chem Biol Source Type: research

Single-molecule trapping and measurement in solution.
Abstract Trapping of a single molecule in the fluid phase was realized decades following developments in the gas-phase, because in some ways the solution phase posed a greater challenge. The key issues have since been addressed by several different means; techniques to confine nanometer scale entities in solution now abound and are gaining traction in a variety of single molecule studies. Available methods range from pure physical entrapment of a molecule on the one hand to electrokinetic and optical techniques, and approaches that exploit thermodynamic principles on the other. Some trapping techniques have also o...
Source: Current Opinion in Chemical Biology - June 26, 2019 Category: Biochemistry Authors: Bespalova MI, Mahanta S, Krishnan M Tags: Curr Opin Chem Biol Source Type: research

Mammalian synthetic biology by CRISPRs engineering and applications.
Abstract Technologies harnessing CRISPR systems have been rapidly evolving and expanding the capacity of researchers for understanding of mammalian cell behavior and its underlying mechanisms through genome and epigenome manipulations. In this review, we summarized the recent developments of CRISPR-based technologies for genetic and epigenetic modifications that include engineering of Cas9 for PAM simplification, non-cleaving base editing tools and alteration of gene expression. Applications such as genome-wide screening methods or CRISPR-based DNA barcoding for cellular lineage tracking are highlighted. Anticipat...
Source: Current Opinion in Chemical Biology - June 26, 2019 Category: Biochemistry Authors: Katayama K, Mitsunobu H, Nishida K Tags: Curr Opin Chem Biol Source Type: research

Extending fluorescence microscopy into anaerobic environments.
Abstract Fluorescence microscopy is a powerful tool for investigating living cells. While widely used fluorescent proteins, such as green fluorescent protein (GFP), have had huge impact in biological imaging because they provide genetically encoded, highly specific labeling, these probes require oxygen to generate fluorescence. This crucial oxidative step has limited the use of GFP-like proteins in anaerobic bacterial systems and restricted live-cell studies of obligate anaerobes and their biology. This review discusses alternative approaches to labeling proteins in anaerobic bacteria that are compatible with live...
Source: Current Opinion in Chemical Biology - June 25, 2019 Category: Biochemistry Authors: Chia HE, Marsh ENG, Biteen JS Tags: Curr Opin Chem Biol Source Type: research

Aptamer-based and aptazyme-based riboswitches in mammalian cells.
In this report, recent advances in synthetic riboswitches that function in mammalian cells are reviewed focusing on the regulatory mechanisms they exploit such as mRNA degradation, microRNA processing, and programmed ribosomal frameshifting. PMID: 31238268 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - June 22, 2019 Category: Biochemistry Authors: Yokobayashi Y Tags: Curr Opin Chem Biol Source Type: research

Strategies for increasing the throughput of super-resolution microscopies.
ley S Abstract Fluorescence microscopy methods have been developed to circumvent the diffraction limit by exploiting nonlinearities in the interactions between light and fluorophores. Initially, these methods were up to orders of magnitude slower than standard microscopies. In recent years, a wide array of technological advances have increased the throughput of super-resolution microscopies, through parallelization, smart scanning or data processing, and sample expansion. Here, we review recent innovations for increased throughput, some applications that have benefitted from them, and how they could be improved in...
Source: Current Opinion in Chemical Biology - June 15, 2019 Category: Biochemistry Authors: Mahecic D, Testa I, Griffié J, Manley S Tags: Curr Opin Chem Biol Source Type: research

Functional super-resolution microscopy of the cell.
Abstract Recent advances in super-resolution fluorescence microscopy have led to ∼10 nm spatial resolution and profound impact on cell biology and beyond. Here we discuss emerging possibilities to encode functional information of intracellular microenvironments, for example, local pH, small-molecule concentrations, chemical polarity (hydrophobicity), and protein activity, into diverse dimensions of the super-resolution signal, hence a class of approaches we collectively refer to as functional super-resolution microscopy. By adding remarkably rich functional information to the already powerful super-reso...
Source: Current Opinion in Chemical Biology - June 15, 2019 Category: Biochemistry Authors: Yan R, Wang B, Xu K Tags: Curr Opin Chem Biol Source Type: research

DNA barcodes evolve for high-resolution cell lineage tracing.
Abstract Mammalian development involves continuous dynamic processes in which cells propagate, differentiate, orchestrate, and decease to produce high-order functions. Although accurate cell lineage information can provide a strong foundation to understand such complex processes, the cell lineages involved in development of the whole mammalian body remain largely unclear, except for in early embryogenesis, which is observable under a microscope. With CRISPR genome editing, the concept of 'evolving DNA barcodes' has rapidly emerged for large-scale, high-resolution cell lineage tracing, where cell-embedded DNA barco...
Source: Current Opinion in Chemical Biology - June 15, 2019 Category: Biochemistry Authors: Masuyama N, Mori H, Yachie N Tags: Curr Opin Chem Biol Source Type: research

Chemoenzymatic synthesis of glycoproteins.
Abstract The majority of the world's best-selling biotherapeutics are glycoproteins. However their production using cellular expression systems invariably produces inseparable mixtures of materials which differ in their attached carbohydrates. As in many cases correct carbohydrate structure is vital for in vivo efficacy, the development of methods for the production of glycoproteins in homogeneous form has become a significant scientific objective. Here a brief overview of recent progress in the production of homogeneous glycoproteins, including monoclonal antibodies, will be discussed, centring on the use of endo...
Source: Current Opinion in Chemical Biology - June 13, 2019 Category: Biochemistry Authors: Fairbanks AJ Tags: Curr Opin Chem Biol Source Type: research

Image scanning microscopy.
Abstract Image Scanning Microscopy (ISM) has emerged as a successful and robust technique which nearly doubles the spatial resolution of a confocal microscope by simple means. Meanwhile, it has found implementation into several highly successful commercial systems, and it has branched into different experimental realizations. The review gives a brief introduction into the basic principles of ISM, and it reports about recent progress and applications of this new microscopy technique. PMID: 31203139 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - June 12, 2019 Category: Biochemistry Authors: Gregor I, Enderlein J Tags: Curr Opin Chem Biol Source Type: research

Whispering-gallery mode (WGM) sensors: review of established and WGM-based techniques to study protein conformational dynamics.
Abstract Monitoring the conformational dynamics of proteins is crucial for a better understanding of their biological functions. To observe the structural dynamics of proteins, it is often necessary to study each molecule individually. To this end, single-molecule techniques have been developed such as Förster resonance energy transfer and optical tweezers. However, although powerful, these techniques do have their limitations, for example, limited temporal resolution, or necessity for fluorescent labelling, and they can often only access a limited set of all protein motions. Here, within the context of estab...
Source: Current Opinion in Chemical Biology - June 12, 2019 Category: Biochemistry Authors: Frustaci S, Vollmer F Tags: Curr Opin Chem Biol Source Type: research

DNA event recorders send past information of cells to the time of observation.
Abstract While current omics and single cell technologies have enabled measurements of high-resolution molecular snapshots of cells at a large scale, these technologies all require destruction of samples and prevent us from analyzing dynamic changes in molecular profiles, phenotypes, and behaviors of individual cells in a complex system. One possible direction to overcome this issue is the development of a cell-embedded 'event recorder' system, whereby molecular and phenotypic information of a cell(s) can be obtained at the time of observation with their past event information stored in 'heritable polymers' of the...
Source: Current Opinion in Chemical Biology - June 11, 2019 Category: Biochemistry Authors: Ishiguro S, Mori H, Yachie N Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: From the iceman to modern medicine.
PMID: 31178257 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - June 6, 2019 Category: Biochemistry Authors: Aye Y, Hergenrother PJ Tags: Curr Opin Chem Biol Source Type: research

Bacterial carbohydrate diversity - a Brave New World.
Abstract Glycans and glycoconjugates feature on the 'front line' of bacterial cells, playing critical roles in the mechanical and chemical stability of the microorganisms, and orchestrating interactions with the environment and all other living organisms. To negotiate such central tasks, bacterial glycomes incorporate a dizzying array of carbohydrate building blocks and non-carbohydrate modifications, which create opportunities for infinite structural variation. This review highlights some of the challenges and opportunities for the chemical biology community in the field of bacterial glycobiology. PMID: 3117...
Source: Current Opinion in Chemical Biology - June 5, 2019 Category: Biochemistry Authors: Imperiali B Tags: Curr Opin Chem Biol Source Type: research

Tag and release: strategies for the intracellular cleavage of protein conjugates.
Abstract Attaching a functional moiety to a protein is required for a wealth of applications, comprising targeted delivery, controlling of enzyme activity, and prodrug-based therapy. Targeting intracellular processes requires the cellular delivery of the protein. While at first, a stable connection between the protein and the modification is desired, once inside the cell, the conjugate might be cleaved again to restore or activate the function of the individual parts. This can be achieved by employing cleavable linkages in conjugates, which are responsive to chemical or enzymatic stimuli inside cells. In this over...
Source: Current Opinion in Chemical Biology - May 31, 2019 Category: Biochemistry Authors: Baumann AL, Hackenberger CPR Tags: Curr Opin Chem Biol Source Type: research

Protein-based parts and devices that respond to intracellular and extracellular signals in mammalian cells.
Abstract Synthetic biology aims to rewire cellular activities and functionality by implementing genetic circuits with high biocomputing capabilities. Recent efforts led to the development of smart sensing interfaces which integrate multiple inputs to activate desired outputs in a highly specific and sensitive manner. In this review, we highlight protein-based interfaces that sense intracellular or extracellular cues providing information about dynamic environmental changes and cellular state. We will also discuss different mechanisms of regulation of gene expression connected to the sensors to develop diagnostic a...
Source: Current Opinion in Chemical Biology - May 31, 2019 Category: Biochemistry Authors: Cella F, Siciliano V Tags: Curr Opin Chem Biol Source Type: research

Chemically induced cell fate reprogramming and the acquisition of plasticity in somatic cells.
Abstract The nature of somatic cell fate has always been considered relatively unchangeable. Only in rare cases, in response to highly specific environmental cues, do differentiated mammalian somatic cells transform into other cell types. However, the fact that cell fate reprogramming can be accomplished by utilizing chemical cocktails, in the absence of any genetic alterations, suggests that the fate determination of somatic cells is much more malleable than previously believed. The use of chemical cocktails to directly alter cell fate sheds light on an important, yet less explored approach to regenerative medici...
Source: Current Opinion in Chemical Biology - May 29, 2019 Category: Biochemistry Authors: Zhao Y Tags: Curr Opin Chem Biol Source Type: research

Engineering cell-cell communication networks: programming multicellular behaviors.
Abstract Cell-cell communication governs the biological behaviors of multicellular populations such as developmental and immunological systems. Thanks to intense genetic analytical studies, the molecular components of cell-cell communication pathways have been well identified. We also have been developing synthetic biology tools to control cellular sensing and response systems that enable engineering of new cell-cell communication with design-based regulatory features. Recently, using these molecular backgrounds, synthetic cellular networks have been built and tested to understand the basic principles of multicell...
Source: Current Opinion in Chemical Biology - May 28, 2019 Category: Biochemistry Authors: Toda S, Frankel NW, Lim WA Tags: Curr Opin Chem Biol Source Type: research

CRISPR/Cas-based devices for mammalian synthetic biology.
Abstract Since its first demonstration for mammalian gene editing, CRISPR/Cas technology has been widely adopted in research, industry, and medicine. Beyond indel mutations induced by Cas9 activity, recent advances in CRISPR/Cas have enabled DNA or RNA base editing. In addition, multiple orthogonal methods for the spatiotemporal regulation of CRISPR/Cas activity and repurposed Cas proteins for the visualization and relocation of specific genomic loci in living cells have been described. By harnessing the versatility of CRISPR/Cas-based devices and gene circuits, synthetic biologists are developing memory devices f...
Source: Current Opinion in Chemical Biology - May 25, 2019 Category: Biochemistry Authors: Kim T, Lu TK Tags: Curr Opin Chem Biol Source Type: research

Mammalian gene circuits with biomolecule-responsive RNA devices.
Abstract Mammalian synthetic gene circuits are promising tools for both biological studies and therapeutic applications. These circuits enable autonomous cellular state-dependent regulation such as the killing of a target cell population. Biomolecule-responsive RNA devices are preferred components of mammalian synthetic gene circuits, because they enable cell-specific gene regulation with a low risk of insertional mutagenesis. In addition, because the output of one RNA device can be the input of another RNA device, synthetic biologists can construct layered gene circuits for more sophisticated regulation. In this ...
Source: Current Opinion in Chemical Biology - May 23, 2019 Category: Biochemistry Authors: Nakanishi H, Saito H Tags: Curr Opin Chem Biol Source Type: research

New players in phototherapy: photopharmacology and bio-integrated optoelectronics.
Abstract 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...
Source: Current Opinion in Chemical Biology - May 17, 2019 Category: Biochemistry Authors: Morstein J, Trauner D Tags: Curr Opin Chem Biol Source Type: research

Synthetic developmental biology: build and control multicellular systems.
Abstract Synthetic biology offers a bottom-up engineering approach that intends to understand complex systems via design-build-test cycles. Embryonic development comprises complex processes that originate at the level of gene regulatory networks in a cell and emerge into collective cellular behaviors with multicellular forms and functions. Here, we review synthetic biology approaches to development that involve building de novo developmental trajectories or engineering control in stem cell-derived multicellular systems. The field of synthetic developmental biology is rapidly growing with the help of recent advance...
Source: Current Opinion in Chemical Biology - May 15, 2019 Category: Biochemistry Authors: Ebrahimkhani MR, Ebisuya M Tags: Curr Opin Chem Biol Source Type: research

Natural products as chemical tools to dissect complex biology in C. elegans.
Abstract 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 ...
Source: Current Opinion in Chemical Biology - May 15, 2019 Category: Biochemistry Authors: Butcher RA Tags: Curr Opin Chem Biol Source Type: research

Identification and characterization of 'readers' for novel histone modifications.
Abstract Histone readers recognize histone modifications and mediate downstream biological events. A series of strategies to identify new histone readers have been developed and improved recently. Asides from the traditional pull-down methods and protein structure/function based educated guess, crosslinking and high-throughput screening based strategies led to the discovery of many new histone readers. In this review, we reviewed the rationale and applications of photo-affinity lysine based crosslinking strategies and array/designer nucleosome libraries based high-throughput screening strategies. Epigenome editing...
Source: Current Opinion in Chemical Biology - May 10, 2019 Category: Biochemistry Authors: Zhao S, Yue Y, Li Y, Li H Tags: Curr Opin Chem Biol Source Type: research

Genetically encoded fragment-based discovery.
Abstract 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 specificit...
Source: Current Opinion in Chemical Biology - April 30, 2019 Category: Biochemistry Authors: Derda R, Ng S Tags: Curr Opin Chem Biol Source Type: research

Pharmacokinetic-pharmacodynamic models that incorporate drug-target binding kinetics.
Abstract 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 tim...
Source: Current Opinion in Chemical Biology - April 25, 2019 Category: Biochemistry Authors: Daryaee F, Tonge PJ Tags: Curr Opin Chem Biol Source Type: research

Targeting defective proteostasis in the collagenopathies.
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. PMID: 31028939 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - April 24, 2019 Category: Biochemistry Authors: Wong MY, Shoulders MD Tags: Curr Opin Chem Biol Source Type: research

Will morphing boron-based inhibitors beat the β-lactamases?
Will morphing boron-based inhibitors beat the β-lactamases? Curr Opin Chem Biol. 2019 Apr 17;50:101-110 Authors: Krajnc A, Lang PA, Panduwawala TD, Brem J, Schofield CJ Abstract 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 a...
Source: Current Opinion in Chemical Biology - April 17, 2019 Category: Biochemistry Authors: Krajnc A, Lang PA, Panduwawala TD, Brem J, Schofield CJ Tags: Curr Opin Chem Biol Source Type: research

Targeted protein degradation: elements of PROTAC design.
Abstract 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. ...
Source: Current Opinion in Chemical Biology - April 16, 2019 Category: Biochemistry Authors: Paiva SL, Crews CM Tags: Curr Opin Chem Biol Source Type: research

Histone deacetylases as an epigenetic pillar for the development of hybrid inhibitors in cancer.
Abstract 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 ...
Source: Current Opinion in Chemical Biology - April 12, 2019 Category: Biochemistry Authors: Stazi G, Fioravanti R, Mai A, Mattevi A, Valente S Tags: Curr Opin Chem Biol Source Type: research

Recent advances in the development of HBV capsid assembly modulators.
Abstract 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 CA...
Source: Current Opinion in Chemical Biology - April 2, 2019 Category: Biochemistry Authors: Nijampatnam B, Liotta DC Tags: Curr Opin Chem Biol Source Type: research

Label-free target identification in drug discovery via phenotypic screening.
Abstract 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 therm...
Source: Current Opinion in Chemical Biology - March 29, 2019 Category: Biochemistry Authors: Park H, Ha J, Park SB Tags: Curr Opin Chem Biol Source Type: research

Developing zebrafish disease models for in vivo small molecule screens.
Abstract 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...
Source: Current Opinion in Chemical Biology - March 28, 2019 Category: Biochemistry Authors: Lam PY, Peterson RT Tags: Curr Opin Chem Biol Source Type: research

Modulating protein-protein interaction networks in protein homeostasis.
Abstract 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. ...
Source: Current Opinion in Chemical Biology - March 23, 2019 Category: Biochemistry Authors: Zhong M, Lee GM, Sijbesma E, Ottmann C, Arkin MR Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: Emergent lessons from the elements of life.
PMID: 30910469 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - March 22, 2019 Category: Biochemistry Authors: Lancaster KM Tags: Curr Opin Chem Biol Source Type: research

Genie in a bottle: controlled release helps tame natural polypharmacology?
Abstract Ability to faithfully report drug-target interactions constitutes a major critical parameter in preclinical/clinical settings. Yet the assessment of target engagement remains challenging, particularly for promiscuous and/or polypharmacologic ligands. Drawing from our improved insights into native electrophile signaling and emerging technologies that profile and interrogate these non-enzyme-assisted signaling subsystems, we posit that 'trained' polypharmocologic covalent inhibitors can be designed. Accumulating evidence indicates that electrophile-modified states at fractional occupancy can alter cell fate...
Source: Current Opinion in Chemical Biology - March 22, 2019 Category: Biochemistry Authors: Long MJ, Liu X, Aye Y Tags: Curr Opin Chem Biol Source Type: research

Using chemical inhibitors to probe AAA protein conformational dynamics and cellular functions.
Abstract 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 f...
Source: Current Opinion in Chemical Biology - March 22, 2019 Category: Biochemistry Authors: Steinman JB, Kapoor TM Tags: Curr Opin Chem Biol Source Type: research

Chemical biology approaches targeting the actin cytoskeleton through phenotypic screening.
Abstract The actin cytoskeleton is dysregulated in cancer, yet this critical cellular machinery has not translated as a druggable clinical target due to cardio-toxic side-effects. Many actin regulators are also considered undruggable, being structural proteins lacking clear functional sites suitable for targeted drug design. In this review, we discuss opportunities and challenges associated with drugging the actin cytoskeleton through its structural regulators, taking tropomyosins as a target example. In particular, we highlight emerging data acquisition and analysis trends driving phenotypic, imaging-based compou...
Source: Current Opinion in Chemical Biology - March 19, 2019 Category: Biochemistry Authors: Bryce NS, Hardeman EC, Gunning PW, Lock JG Tags: Curr Opin Chem Biol Source Type: research

Sphingolipids and membrane targets for therapeutics.
Abstract 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 b...
Source: Current Opinion in Chemical Biology - March 18, 2019 Category: Biochemistry Authors: Loewith R, Riezman H, Winssinger N Tags: Curr Opin Chem Biol Source Type: research

Reactive-cysteine profiling for drug discovery.
Abstract 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 pro...
Source: Current Opinion in Chemical Biology - March 18, 2019 Category: Biochemistry Authors: Maurais AJ, Weerapana E Tags: Curr Opin Chem Biol Source Type: research

Editorial overview: New pieces in the redox puzzle: oxidative and reductive transformations in biotechnology.
PMID: 30885748 [PubMed - as supplied by publisher] (Source: Current Opinion in Chemical Biology)
Source: Current Opinion in Chemical Biology - March 15, 2019 Category: Biochemistry Authors: Vincent KA, Nestl BM Tags: Curr Opin Chem Biol Source Type: research