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1.
Dr. Jonathan W. Bogart Dr. Maria D. Cabezas Dr. Bastian Vögeli Derek A. Wong Dr. Ashty S. Karim Prof. Dr. Michael C. Jewett 《Chembiochem : a European journal of chemical biology》2021,22(1):84-91
Natural products and secondary metabolites comprise an indispensable resource from living organisms that have transformed areas of medicine, agriculture, and biotechnology. Recent advances in high-throughput DNA sequencing and computational analysis suggest that the vast majority of natural products remain undiscovered. To accelerate the natural product discovery pipeline, cell-free metabolic engineering approaches used to develop robust catalytic networks are being repurposed to access new chemical scaffolds, and new enzymes capable of performing diverse chemistries. Such enzymes could serve as flexible biocatalytic tools to further expand the unique chemical space of natural products and secondary metabolites, and provide a more sustainable route to manufacture these molecules. Herein, we highlight select examples of natural product biosynthesis using cell-free systems and propose how cell-free technologies could facilitate our ability to access and modify these structures to transform synthetic and chemical biology. 相似文献
2.
Robinette SL Brüschweiler R Schroeder FC Edison AS 《Accounts of chemical research》2012,45(2):288-297
Small molecules are central to biology, mediating critical phenomena such as metabolism, signal transduction, mating attraction, and chemical defense. The traditional categories that define small molecules, such as metabolite, secondary metabolite, pheromone, hormone, and so forth, often overlap, and a single compound can appear under more than one functional heading. Therefore, we favor a unifying term, biogenic small molecules (BSMs), to describe any small molecule from a biological source. In a similar vein, two major fields of chemical research,natural products chemistry and metabolomics, have as their goal the identification of BSMs, either as a purified active compound (natural products chemistry) or as a biomarker of a particular biological state (metabolomics). Natural products chemistry has a long tradition of sophisticated techniques that allow identification of complex BSMs, but it often fails when dealing with complex mixtures. Metabolomics thrives with mixtures and uses the power of statistical analysis to isolate the proverbial "needle from a haystack", but it is often limited in the identification of active BSMs. We argue that the two fields of natural products chemistry and metabolomics have largely overlapping objectives: the identification of structures and functions of BSMs, which in nature almost inevitably occur as complex mixtures. Nuclear magnetic resonance (NMR) spectroscopy is a central analytical technique common to most areas of BSM research. In this Account, we highlight several different NMR approaches to mixture analysis that illustrate the commonalities between traditional natural products chemistry and metabolomics. The primary focus here is two-dimensional (2D) NMR; because of space limitations, we do not discuss several other important techniques, including hyphenated methods that combine NMR with mass spectrometry and chromatography. We first describe the simplest approach of analyzing 2D NMR spectra of unfractionated mixtures to identify BSMs that are unstable to chemical isolation. We then show how the statistical method of covariance can be used to enhance the resolution of 2D NMR spectra and facilitate the semi-automated identification of individual components in a complex mixture. Comparative studies can be used with two or more samples, such as active vs inactive, diseased vs healthy, treated vs untreated, wild type vs mutant, and so on. We present two overall approaches to comparative studies: a simple but powerful method for comparing two 2D NMR spectra and a full statistical approach using multiple samples. The major bottleneck in all of these techniques is the rapid and reliable identification of unknown BSMs; the solution will require all the traditional approaches of both natural products chemistry and metabolomics as well as improved analytical methods, databases, and statistical tools. 相似文献
3.
This Account provides an overview and examples of function-oriented synthesis (FOS) and its increasingly important role in producing therapeutic leads that can be made in a step-economical fashion. Biologically active natural product leads often suffer from several deficiencies. Many are scarce or difficult to obtain from natural sources. Often, they are highly complex molecules and thus not amenable to a practical synthesis that would impact supply. Most are not optimally suitable for human therapeutic use. The central principle of FOS is that the function of a biologically active lead structure can be recapitulated, tuned, or greatly enhanced with simpler scaffolds designed for ease of synthesis and also synthetic innovation. This approach can provide practical access to new (designed) structures with novel activities while at the same time allowing for synthetic innovation by target design. This FOS approach has been applied to a number of therapeutically important natural product leads. For example, bryostatin is a unique natural product anticancer lead that restores apoptosis in cancer cells, reverses multidrug resistance, and bolsters the immune system. Remarkably, it also improves cognition and memory in animals. We have designed and synthesized simplified analogs of bryostatin that can be made in a practical fashion (pilot scale) and are superior to bryostatin in numerous assays including growth inhibition in a variety of human cancer cell lines and in animal models. Laulimalide is another exciting anticancer lead that stabilizes microtubules, like paclitaxel, but unlike paclitaxel, it is effective against multidrug-resistant cell lines. Laulimalide suffers from availability and stability problems, issues that have been addressed using FOS through the design and synthesis of stable and efficacious laulimalide analogs. Another FOS program has been directed at the design and synthesis of drug delivery systems for enabling or enhancing the uptake of drugs or drug candidates into cells and tissue. We have generated improved transporters that can deliver agents in a superior fashion compared with naturally occurring cell-penetrating peptides and that can be synthesized in a practical and step-economical fashion. The use of FOS has allowed for the translation of exciting, biologically active natural product leads into simplified analogs with superior function. This approach enables the development of synthetically innovative strategies while targeting therapeutically novel structures. 相似文献
4.
Jone Iriondo‐Alberdi Dr. Katta Laxmi‐Reddy Dr. Benaissa Bouguerne Cathy Staedel Dr. Ivan Huc Dr. 《Chembiochem : a European journal of chemical biology》2010,11(12):1679-1685
The intracellular transport of drugs and therapeutics represents one of the most exciting and challenging areas at the interface of chemistry, biology, and medicine. Most of the effort in this field so far has been devoted to the development of peptide‐based delivery systems that can translocate therapeutic agents into their intracellular targets. More recently, the use of bioinspired non‐natural foldamers has resulted in the successful delivery of cargo molecules, which possess a wide range of sizes and physicochemical properties across the cell membrane. We report herein the synthesis of aromatic amide foldamers and their biological evaluation as cell‐penetrating agents. By using a well‐established synthetic route, a series of fluorescein‐labeled cationic aryl amide conjugates has been constructed, and their cellular uptake into various human cell lines has been analyzed by flow cytometry and fluorescence microscopy. The assays revealed that longer oligomers achieve greater cellular translocation, with octamer Q8 proving to be a remarkable vehicle for all three cell lines. Biological studies have also indicated that these helices are biocompatible, thus showing promise in their application as cell‐penetrating agents and as vehicles to deliver biologically active molecules into cells. 相似文献
5.
Lech‐Gustav Milroy Dr. Giovanna Zinzalla Dr. François Loiseau Dr. Zizheng Qian Giuseppe Prencipe Chris Pepper Dr. Chris Fegan Dr. Steven V. Ley Prof. Dr. 《ChemMedChem》2008,3(12):1922-1935
B‐cell chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in the Western world for which no curative treatments are currently available. Purine nucleotide analogues and alkylating agents feature frequently in combination regimens to treat the malignant state, but their use has not led to any significant improvement in patient survival. Consequently, there still remains a need for alternative small‐molecule chemotherapeutics. Natural products are an unparalleled source of drug leads, and an unending inspiration for the design of small‐molecule libraries for drug discovery. The screening of focused libraries of natural‐product‐like spiroketal and fused bicyclic acetal small molecules against primary CLL cells has led to the identification of a small series of novel and potent cytotoxic agents towards primary CLL cells. The validation of the activity of these molecules is delineated through a series of synthesis and screening iterations, whereas preliminary mode of action studies positively indicate their ability to induce cell death via an apoptotic pathway with no evidence of necrosis to further support their potential as novel chemotherapeutic agents. 相似文献
6.
Design and application of stimulus-responsive peptide systems 总被引:1,自引:0,他引:1
The ability of peptides and proteins to change conformations in response to external stimuli such as temperature, pH and the presence of specific small molecules is ubiquitous in nature. Exploiting this phenomenon, numerous natural and designed peptides have been used to engineer stimulus-responsive systems with potential applications in important research areas such as biomaterials, nanodevices, biosensors, bioseparations, tissue engineering and drug delivery. This review describes prominent examples of both natural and designed synthetic stimulus-responsive peptide systems. While the future looks bright for stimulus-responsive systems based on natural and rationally engineered peptides, it is expected that the range of stimulants used to manipulate such systems will be significantly broadened through the use of combinatorial protein engineering approaches such as directed evolution. These new proteins and peptides will continue to be employed in exciting and high-impact research areas including bionanotechnology and synthetic biology. 相似文献
7.
Dr. Hannah K. D'Ambrosio Aaron M. Keeler Prof. Emily R. Derbyshire 《Chembiochem : a European journal of chemical biology》2023,24(17):e202300263
Natural product discovery has traditionally relied on the isolation of small molecules from producing species, but genome-sequencing technology and advances in molecular biology techniques have expanded efforts to a wider array of organisms. Protists represent an underexplored kingdom for specialized metabolite searches despite bioinformatic analysis that suggests they harbor distinct biologically active small molecules. Specifically, pathogenic apicomplexan parasites, responsible for billions of global infections, have been found to possess multiple biosynthetic gene clusters, which hints at their capacity to produce polyketide metabolites. Biochemical studies have revealed unique features of apicomplexan polyketide synthases, but to date, the identity and function of the polyketides synthesized by these megaenzymes remains unknown. Herein, we discuss the potential for specialized metabolite production in protists and the possible evolution of polyketide biosynthetic gene clusters in apicomplexan parasites. We then focus on a polyketide synthase from the apicomplexan Toxoplasma gondii to discuss the unique domain architecture and properties of these proteins when compared to previously characterized systems, and further speculate on the possible functions for polyketides in these pathogenic parasites. 相似文献
8.
Harrison Ndungu Mwangi Edward Kirwa Muge Peter Waiganjo Wagacha Albert Ndakala Francis Jackim Mulaa 《International journal of molecular sciences》2021,22(9)
The development of novel anti-infectives against Kinetoplastids pathogens targeting proteins is a big problem occasioned by the antigenic variation in these parasites. This is also a global concern due to the zoonosis of these parasites, as they infect both humans and animals. Therefore, we need not only to create novel antibiotics, but also to speed up the development pipeline for these antibiotics. This may be achieved by using novel drug targets for Kinetoplastids drug discovery. In this study, we focused our attention on motifs of rRNA molecules that have been created using homology modeling. The RNA is the most ambiguous biopolymer in the kinetoplatid, which carries many different functions. For instance, tRNAs, rRNAs, and mRNAs are essential for gene expression both in the pro-and eukaryotes. However, all these types of RNAs have sequences with unique 3D structures that are specific for kinetoplastids only and can be used to shut down essential biochemical processes in kinetoplastids only. All these features make RNA very potent targets for antibacterial drug development. Here, we combine in silico methods combined with both computational biology and structure prediction tools to address our hypothesis. In this study, we outline a systematic approach for identifying kinetoplastid rRNA-ligand interactions and, more specifically, techniques that can be used to identify small molecules that target particular RNA. The high-resolution optimized model structures of these kineoplastids were generated using RNA 123, where all the stereochemical conflicts were solved and energies minimized to attain the best biological qualities. The high-resolution optimized model’s structures of these kinetoplastids were generated using RNA 123 where all the stereochemical conflicts were solved and energies minimized to attain the best biological qualities. These models were further analyzed to give their docking assessment reliability. Docking strategies, virtual screening, and fishing approaches successfully recognized novel and myriad macromolecular targets for the myxobacterial natural products with high binding affinities to exploit the unmet therapeutic needs. We demonstrate a sensible exploitation of virtual screening strategies to 18S rRNA using natural products interfaced with classical maximization of their efficacy in phamacognosy strategies that are well established. Integration of these virtual screening strategies in natural products chemistry and biochemistry research will spur the development of potential interventions to these tropical neglected diseases. 相似文献
9.
Dr. Elena Lenci Prof. Andrea Trabocchi 《Chembiochem : a European journal of chemical biology》2019,20(9):1115-1123
Synthetic chemists are always looking for new methods to maximize the diversity and complexity of small-molecule libraries. Diversity-oriented synthesis can give access to new chemotypes with high chemical diversity, exploiting complexity-generating reactions and divergent approaches. However, there is a need for new tools to drive synthetic efforts towards unexplored and biologically relevant regions of chemical space. Because the number of publicly accessible biological data will increase in the years to come, cheminformatics can represent a real opportunity to develop better chemical libraries. This minireview focuses on novel cheminformatics approaches used to design molecular scaffolds, as well as to analyze their quality, giving a perspective of them in the field of chemical biology and drug discovery through some selected case studies. 相似文献
10.
Dr. Maria Duca Dr. Dennis Gillingham Prof. Dr. Christian Adam Olsen Prof. Dr. Gianluca Sbardella Dr. Philip R. Skaanderup Prof. Dr. Mario van der Stelt Prof. Dr. Boris Vauzeilles Prof. Dr. Olalla Vázquez Dr. Yves P. Auberson 《Chembiochem : a European journal of chemical biology》2021,22(19):2823-2825
The E uropean F ederation for M edicinal chemistry and C hemical biology (EFMC) is a federation of learned societies. It groups organizations of European scientists working in a dynamic field spanning chemical biology and medicinal chemistry. New ideas, tools, and technologies emerging from a wide array of scientific disciplines continuously energize this rapidly evolving area. Medicinal chemistry is the design, synthesis, and optimization of biologically active molecules aimed at discovering new drug candidates – a mission that in many ways overlaps with the scope of chemical biology. Chemical biology is by now a mature field of science for which a more precise definition of what it encompasses, in the frame of EFMC, is timely. This article discusses chemical biology as currently understood by EFMC, including all activities dealing with the design and synthesis of biologically active chemical tools and their use to probe, characterize, or influence biological systems. 相似文献
11.
Syed Adnan Ali Shah Huey Ling Tan Sadia Sultan Muhammad Afifi Bin Mohd Faridz Mohamad Azlan Bin Mohd Shah Sharifah Nurfazilah Munawar Hussain 《International journal of molecular sciences》2014,15(7):12027-12060
Microbial-catalyzed biotransformations have considerable potential for the generation of an enormous variety of structurally diversified organic compounds, especially natural products with complex structures like triterpenoids. They offer efficient and economical ways to produce semi-synthetic analogues and novel lead molecules. Microorganisms such as bacteria and fungi could catalyze chemo-, regio- and stereospecific hydroxylations of diverse triterpenoid substrates that are extremely difficult to produce by chemical routes. During recent years, considerable research has been performed on the microbial transformation of bioactive triterpenoids, in order to obtain biologically active molecules with diverse structures features. This article reviews the microbial modifications of tetranortriterpenoids, tetracyclic triterpenoids and pentacyclic triterpenoids. 相似文献
12.
Dr. Katherine Williams Dr. Claudio Greco Dr. Andrew M. Bailey Prof. Christine L. Willis 《Chembiochem : a European journal of chemical biology》2021,22(21):3027-3036
Azaphilones are a family of polyketide-based fungal natural products that exhibit interesting and useful bioactivities. This minireview explores the literature on various characterised azaphilone biosynthetic pathways, which allows for a proposed consensus scheme for the production of the core azaphilone structure, as well as identifying early diversification steps during azaphilone biosynthesis. A consensus understanding of the core enzymatic steps towards a particular family of fungal natural products can aid in genome-mining experiments. Genome mining for novel fungal natural products is a powerful technique for both exploring chemical space and providing new insights into fungal natural product pathways. 相似文献
13.
稳定的活性物载体--葡糖微球 总被引:1,自引:0,他引:1
系统介绍了法国蔻波公司研制开发的一种新型释放体系-葡糖微球。葡糖微球具有独物的仿生结构-围绕一个固态内核排列的超分子,分别通过离子链和疏水作用来包裹和保护亲油性和亲水性的化妆品洗性成分。经测试具有优异的防止如维生素或酶等易变分子的降解,保持被包裹物活性的功效。因其独特的释放体系,很小的粒径被成功地应用于表皮上层活性成分的保持和传输。 相似文献
14.
Colloidal microcrystalline cellulose, introduced in 1961, now is a successful commercial product with growing world-wide markets. This paper describes some major findings of our continuing research to convert fibrous or fiber-forming polymer systems into new colloidal microcrystalline physical states without going through a homogeneous molecular solution phase. Several novel microcrystalline colloidal products from the following natural and/or synthetic polymeric raw materials are described and compared for the first time: cellulose, amylose, collagen, nylon, and chrysotile mineral silicates. Many previously unpublished electron micrographs are presented. These products demonstrate a new and growing field of colloidal microcrystalline polymer science. They open up increasing opportunities for new polymer products based on the original concept, namely, the unhinging of polymer microcrystals from their natural or synthetic network and then by appropriate mechanical energy, releasing them as discrete, submicron colloidal polymer microcrystals dispersed in various liquid media to form unique gel systems, or reaggregated in the dry state to form porous colloidal particles. 相似文献
15.
Muhammad Wajid Ullah Mazhar Ul Islam Shaukat Khan Nasrullah Shah Joong Kon Park 《Korean Journal of Chemical Engineering》2017,34(6):1591-1599
Conventional approaches of regulating natural biochemical and biological processes are greatly hampered by the complexity of natural systems. Therefore, current biotechnological research is focused on improving biological systems and processes using advanced technologies such as genetic and metabolic engineering. These technologies, which employ principles of synthetic and systems biology, are greatly motivated by the diversity of living organisms to improve biological processes and allow the manipulation and reprogramming of target bioreactions and cellular systems. This review describes recent developments in cell biology, as well as genetic and metabolic engineering, and their role in enhancing biological processes. In particular, we illustrate recent advancements in genetic and metabolic engineering with respect to the production of bacterial cellulose (BC) using the model systems Gluconacetobacter xylinum and Gluconacetobacter hansenii. Besides, the cell-free enzyme system, representing the latest engineering strategies, has been comprehensively described. The content covered in the current review will lead readers to get an insight into developing novel metabolic pathways and engineering novel strains for enhanced production of BC and other bioproducts formation. 相似文献
16.
April L. Lukowski Prof. Alison R. H. Narayan 《Chembiochem : a European journal of chemical biology》2019,20(10):1231-1241
Natural product biosynthetic pathways are composed of enzymes that use powerful chemistry to assemble complex molecules. Small molecule neurotoxins are examples of natural products with intricate scaffolds which often have high affinities for their biological targets. The focus of this Minireview is small molecule neurotoxins targeting voltage-gated sodium channels (VGSCs) and the state of knowledge on their associated biosynthetic pathways. There are three small molecule neurotoxin receptor sites on VGSCs associated with three different classes of molecules: guanidinium toxins, alkaloid toxins, and ladder polyethers. Each of these types of toxins have unique structural features which are assembled by biosynthetic enzymes and the extent of information known about these enzymes varies among each class. The biosynthetic enzymes involved in the formation of these toxins have the potential to become useful tools in the efficient synthesis of VGSC probes. 相似文献
17.
介绍了天然界中存在很多含有噻唑/(口恶)唑结构单元的活性分子,其生物合成途径或仿生合成方法通常分别以多肽氨基酸残基的羧酸基团或羧酸衍生物为底物,与半胱氨酸/丝氨酸等天然氨基酸或经过衍生化的非天然氨基酸环合、氧化而成,因此天然产物中的噻唑/(口恶)唑C5位通常以无取代的形式存在。然而,C5位二聚化、烯基化或芳基化的噻唑/(口恶)唑结构单元常见于具有广泛药理活性的人工合成的分子中,构建这类结构单元通常都需预先制备β-取代的非天然氨基酸。并且,关于该类天然产物的结构改造均未涉及噻唑/(口恶)唑C5位上的官能团化修饰,这是由于目前尚缺乏该位点上的官能团化方法而造成的。该现状预示着,开发噻唑/(口恶)唑C5位官能团化新方法,并将其应用于噻唑/(口恶)唑天然产物的结构修饰,具有十分重要的意义和研究价值。 相似文献
18.
Dr. Manuel Nieto-Domínguez Dr. Pablo I. Nikel 《Chembiochem : a European journal of chemical biology》2020,21(18):2551-2571
The diversity of life relies on a handful of chemical elements (carbon, oxygen, hydrogen, nitrogen, sulfur and phosphorus) as part of essential building blocks; some other atoms are needed to a lesser extent, but most of the remaining elements are excluded from biology. This circumstance limits the scope of biochemical reactions in extant metabolism – yet it offers a phenomenal playground for synthetic biology. Xenobiology aims to bring novel bricks to life that could be exploited for (xeno)metabolite synthesis. In particular, the assembly of novel pathways engineered to handle nonbiological elements (neometabolism) will broaden chemical space beyond the reach of natural evolution. In this review, xeno-elements that could be blended into nature's biosynthetic portfolio are discussed together with their physicochemical properties and tools and strategies to incorporate them into biochemistry. We argue that current bioproduction methods can be revolutionized by bridging xenobiology and neometabolism for the synthesis of new-to-nature molecules, such as organohalides. 相似文献
19.
Recent trends in the synthesis of organo-fluorine compounds using the conventional selective electrochemical fluorination
(SEF) route as well as other novel synthetic approaches are presented. In the conventional SEF route, fluorinations of the
active methylene group in the side chain as well as unsaturated alkenes have been achieved. In the case of heterocycles, nuclear
fluorination is the predominant process. In aromatic compounds, nuclear substitution as well as addition proceeds simultaneously,
leading to the formation of a mixture of products. The influence of solvents, supporting electrolytes and adsorption on product
yield and selectivity has also been evaluated in recent studies. DME is found to be a superior solvent for the above processes.
In the SEF process itself, redox mediators have been employed to minimize passivation and achieve better current efficiencies.
Nitrogen bases containing perfluoro alkyl unit have been synthesized using redox catalysts as mediators and trifluoromethylation
was achieved by the sacrificial anode technique. The introduction of the trimethyl silyl (TMS) group into the −CF3 moiety to form very reactive −CF2—TMS synthon, leads to the synthesis of interesting organic molecules. A brief summary of important biologically active fluoro
organic molecules that have been prepared by the electrochemical route is also provided. 相似文献
20.
Automated Identification of Depsipeptide Natural Products by an Informatic Search Algorithm
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Michael A. Skinnider Chad W. Johnston Rostyslav Zvanych Prof. Nathan A. Magarvey 《Chembiochem : a European journal of chemical biology》2015,16(2):223-227
Nonribosomal depsipeptides are a class of potent microbial natural products, which include several clinically approved pharmaceutical agents. Genome sequencing has revealed a large number of uninvestigated natural‐product biosynthetic gene clusters. However, while novel informatic search methods to access these gene clusters have been developed to identify peptide natural products, depsipeptide detection has proven challenging. Herein, we present an improved version of our informatic search algorithm for natural products (iSNAP), which facilitates the detection of known and genetically predicted depsipeptides in complex microbial culture extracts. We validated this technology by identifying several depsipeptides from novel producers, and located a large number of novel depsipeptide gene clusters for future study. This approach highlights the value of chemoinformatic search methods for the discovery of genetically encoded metabolites by targeting specific areas of chemical space. 相似文献