RESUMEN
Sponges (Porifera) contain many peptide-specialized metabolites with potent biological activities and significant roles in shaping marine ecology. It is well established that symbiotic bacteria produce bioactive "sponge" peptides, both on the ribosome (RiPPs) and nonribosomally. Here, we demonstrate that sponges themselves also produce many bioactive macrocyclic peptides, such as phakellistatins and related proline-rich macrocyclic peptides (PRMPs). Using the Stylissa carteri sponge transcriptome, methods were developed to find sequences encoding 46 distinct RiPP-type core peptides, of which ten encoded previously identified PRMP sequences. With this basis set, the genome and transcriptome of the sponge Axinella corrugata was interrogated to find 35 PRMP precursor peptides encoding 31 unique core peptide sequences. At least 11 of these produced cyclic peptides that were present in the sponge and could be characterized by mass spectrometry, including stylissamides A-D and seven previously undescribed compounds. Precursor peptides were encoded in the A. corrugata genome, confirming their animal origin. The peptides contained signal peptide sequences and highly repetitive recognition sequence-core peptide elements with up to 25 PRMP copies in a single precursor. In comparison to sponges without PRMPs, PRMP sponges are incredibly enriched in potentially secreted polypeptides, with >23,000 individual signal peptide encoding genes found in a single transcriptome. The similarities between PRMP biosynthetic genes and neuropeptides in terms of their biosynthetic logic suggest a fundamental biology linked to circular peptides, possibly indicating a widespread and underappreciated diversity of signaling peptide post-translational modifications across the animal kingdom.
Asunto(s)
Péptidos Cíclicos , Péptidos , Animales , Péptidos/genética , Péptidos Cíclicos/genética , Secuencia de Aminoácidos , Vendajes , Señales de Clasificación de ProteínaRESUMEN
Lipopeptides represent a large group of microbial natural products that include important antibacterial and antifungal drugs and some of the most-powerful known biosurfactants. The vast majority of lipopeptides comprise cyclic peptide backbones N-terminally equipped with various fatty acyl moieties. The known compounds of this type are biosynthesized by nonribosomal peptide synthetases, giant enzyme complexes that assemble their products in a non-gene-encoded manner. Here, we report the genome-guided discovery of ribosomally derived, fatty-acylated lipopeptides, termed selidamides. Heterologous reconstitution of three pathways, two from cyanobacteria and one from an arctic, ocean-derived alphaproteobacterium, allowed structural characterization of the probable natural products and suggest that selidamides are widespread over various bacterial phyla. The identified representatives feature cyclic peptide moieties and fatty acyl units attached to (hydroxy)ornithine or lysine side chains by maturases of the GCN5-related N-acetyltransferase superfamily. In contrast to nonribosomal lipopeptides that are usually produced as congener mixtures, the three selidamides are selectively fatty acylated with C10, C12, or C16 fatty acids, respectively. These results highlight the ability of ribosomal pathways to emulate products with diverse, nonribosomal-like features and add to the biocatalytic toolbox for peptide drug improvement and targeted discovery.
Asunto(s)
Lipopéptidos/biosíntesis , Lipopéptidos/química , Ribosomas/metabolismo , Antibacterianos/metabolismo , Antifúngicos/metabolismo , Vías Biosintéticas , Cianobacterias/metabolismo , Péptido Sintasas/metabolismo , Péptidos CíclicosRESUMEN
The implementation of several global microbiome studies has yielded extensive insights into the biosynthetic potential of natural microbial communities. However, studies on the distribution of several classes of ribosomally synthesized and post-translationally modified peptides (RiPPs), non-ribosomal peptides (NRPs) and polyketides (PKs) in different large microbial ecosystems have been very limited. Here, we collected a large set of metagenome-assembled bacterial genomes from marine, freshwater and terrestrial ecosystems to investigate the biosynthetic potential of these bacteria. We demonstrate the utility of public dataset collections for revealing the different secondary metabolite biosynthetic potentials among these different living environments. We show that there is a higher occurrence of RiPPs in terrestrial systems, while in marine systems, we found relatively more terpene-, NRP-, and PK encoding gene clusters. Among the many new biosynthetic gene clusters (BGCs) identified, we analyzed various Nif-11-like and nitrile hydratase leader peptide (NHLP) containing gene clusters that would merit further study, including promising products, such as mersacidin-, LAP- and proteusin analogs. This research highlights the significance of public datasets in elucidating the biosynthetic potential of microbes in different living environments and underscores the wide bioengineering opportunities within the RiPP family.
Asunto(s)
Bacterias , Productos Biológicos , Familia de Multigenes , Bacterias/metabolismo , Bacterias/genética , Bacterias/clasificación , Productos Biológicos/metabolismo , Péptidos/metabolismo , Péptidos/genética , Procesamiento Proteico-Postraduccional , Metagenoma , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Ecosistema , Genoma Bacteriano , Microbiota , Policétidos/metabolismoRESUMEN
The ß-hemolytic factor streptolysin S (SLS) is an important linear azol(in)e-containing peptide (LAP) that contributes significantly to the virulence of Streptococcus pyogenes. Despite its discovery 85â years ago, SLS has evaded structural characterizing owing to its notoriously problematic physicochemical properties. Here, we report the discovery and characterization of a structurally analogous hemolytic peptide from Enterococcus caccae, termed enterolysin S (ELS). Through heterologous expression, site-directed mutagenesis, chemoselective modification, and high-resolution mass spectrometry, we found that ELS contains an intriguing contiguous octathiazole moiety. The discovery of ELS expands our knowledge of hemolytic LAPs by adding a new member to this virulence-promoting family of modified peptides.
Asunto(s)
Enterococcus , Enterococcus/metabolismo , Tiazoles/química , Tiazoles/metabolismo , Péptidos/química , Péptidos/metabolismo , Hemólisis/efectos de los fármacos , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Secuencia de AminoácidosRESUMEN
Ribosomally synthesized post-translationally modified peptides (RiPPs) are a novel category of bioactive natural products (NPs). Streptomyces bacteria are a potential source of many bioactive NPs. Limited opportunities are available to characterize all the bioactive NP gene clusters. In this study, 410 sequences of Streptomyces were analyzed for RiPPs through genome mining using the National Center for Biotechnology Information (NCBI), by combining BAGEL and anti-SMASH. A total of 4098 RiPPs were found; including both classified (lanthipeptide, RiPP-like, bacteriocin, LAPs, lassopeptide, thiopeptides) and nonclassified RiPPs. Soil was identified as a rich habitat for RiPPs. These data may offer alternative future remedies for various health issues.
RESUMEN
Cyclic peptides with cyclophane linkers are an attractive compound type owing to the fine-tuned rigid three-dimensional structures and unusual biophysical features. Cytochrome P450 enzymes are capable of catalyzing not only the C-C and C-O oxidative coupling reactions found in vancomycin and other nonribosomal peptides (NRPs), but they also exhibit novel catalytic activities to generate cyclic ribosomally synthesized and post-translationally modified peptides (RiPPs) through cyclophane linkage. To discover more P450-modified multicyclic RiPPs, we set out to find cryptic and unknown P450-modified RiPP biosynthetic gene clusters (BGCs) through genome mining. Synergized bioinformatic analysis reveals that P450-modified RiPP BGCs are broadly distributed in bacteria and can be classified into 11â classes. Focusing on two classes of P450-modified RiPP BGCs where precursor peptides contain multiple conserved aromatic amino acid residues, we characterized 11 novel P450-modified multicyclic RiPPs with different cyclophane linkers through heterologous expression. Further mutation of the key ring-forming residues and combinatorial biosynthesis study revealed the order of bond formation and the specificity of P450s. This study reveals the functional diversity of P450 enzymes involved in the cyclophane-containing RiPPs and indicates that P450 enzymes are promising tools for rapidly obtaining structurally diverse cyclic peptide derivatives.
Asunto(s)
Productos Biológicos , Ciclofanos , Péptidos/química , Péptidos Cíclicos/química , Biología Computacional/métodos , Sistema Enzimático del Citocromo P-450/metabolismo , Procesamiento Proteico-Postraduccional , Productos Biológicos/químicaRESUMEN
In recent years, genome and transcriptome mining have dramatically expanded the rate of discovering diverse natural products from bacteria and fungi. In plants, this approach is often more limited due to the lack of available annotated genomes and transcriptomes combined with a less consistent clustering of biosynthetic genes. The recently identified burpitide class of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products offer a valuable opportunity for bioinformatics-guided discovery in plants due to their short biosynthetic pathways and gene encoded substrates. Using a high-throughput approach to assemble and analyze 700 publicly available raw transcriptomic data sets, we uncover the potential distribution of split burpitide precursor peptides in Streptophyta. Metabolomic analysis of target plants confirms our bioinformatic predictions of new cyclopeptide alkaloids from both known and new sources.
RESUMEN
Derivatizing natural products (NPs) is essential in structure-activity relationship (SAR) studies, compound optimization, and drug development. Ribosomally synthesized and post-translationally modified peptides (RiPPs) represent one of the major classes of natural products. Thioholgamide represents thioamitide - a recently emerged family of RiPPs with unique structures and great potential in anticancer drug development. Although the method for generating the RiPP library by codon substitutions in the precursor peptide gene is straightforward, the techniques to perform RiPP derivatization in Actinobacteria remain limited and time-consuming. Here, we report a facile system for producing a library of randomized thioholgamide derivatives utilizing an optimized Streptomyces host. This technique enabled us to access all possible amino acid substitutions of the thioholgamide molecule, one position at a time. Out of 152 potential derivatives, 85 were successfully detected, revealing the impact of amino acid substitutions on thioholgamide post-translational modifications (PTMs). Moreover, new PTMs were observed among thioholgamide derivatives: thiazoline heterocycles, which have not yet been reported for thioamitides, and S-methylmethionine, which is very rare in nature. The obtained library was subsequently used for thioholgamide SAR studies and stability assays.
Asunto(s)
Productos Biológicos , Streptomyces , Streptomyces/genética , Streptomyces/metabolismo , Péptidos/química , Procesamiento Proteico-Postraduccional , Biblioteca de Genes , Productos Biológicos/metabolismoRESUMEN
Microbial natural products represent a rich resource of evolved chemistry that forms the basis for the majority of pharmacotherapeutics. Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a particularly interesting class of natural products noted for their unique mode of biosynthesis and biological activities. Analyses of sequenced microbial genomes have revealed an enormous number of biosynthetic loci encoding RiPPs but whose products remain cryptic. In parallel, analyses of bacterial metabolomes typically assign chemical structures to only a minority of detected metabolites. Aligning these 2 disparate sources of data could provide a comprehensive strategy for natural product discovery. Here we present DeepRiPP, an integrated genomic and metabolomic platform that employs machine learning to automate the selective discovery and isolation of novel RiPPs. DeepRiPP includes 3 modules. The first, NLPPrecursor, identifies RiPPs independent of genomic context and neighboring biosynthetic genes. The second module, BARLEY, prioritizes loci that encode novel compounds, while the third, CLAMS, automates the isolation of their corresponding products from complex bacterial extracts. DeepRiPP pinpoints target metabolites using large-scale comparative metabolomics analysis across a database of 10,498 extracts generated from 463 strains. We apply the DeepRiPP platform to expand the landscape of novel RiPPs encoded within sequenced genomes and to discover 3 novel RiPPs, whose structures are exactly as predicted by our platform. By building on advances in machine learning technologies, DeepRiPP integrates genomic and metabolomic data to guide the isolation of novel RiPPs in an automated manner.
Asunto(s)
Proteínas Bacterianas/aislamiento & purificación , Productos Biológicos/aislamiento & purificación , Descubrimiento de Drogas/métodos , Péptidos/aislamiento & purificación , Programas Informáticos , Bacterias/genética , Bacterias/metabolismo , Proteínas Bacterianas/biosíntesis , Proteínas Bacterianas/genética , Productos Biológicos/metabolismo , Genómica/métodos , Aprendizaje Automático , Metabolómica/métodos , Biosíntesis de Péptidos/genética , Péptidos/genética , Péptidos/metabolismo , Procesamiento Proteico-Postraduccional , Ribosomas/metabolismoRESUMEN
The emergence of superbugs developing resistance to antibiotics and the resurgence of microbial infections have led scientists to start an antimicrobial arms race. In this context, we have previously identified an active RiPP, the Ruminococcin C1, naturally produced by Ruminococcus gnavus E1, a symbiont of the healthy human intestinal microbiota. This RiPP, subclassified as a sactipeptide, requires the host digestive system to become active against pathogenic Clostridia and multidrug-resistant strains. Here we report its unique compact structure on the basis of four intramolecular thioether bridges with reversed stereochemistry introduced posttranslationally by a specific radical-SAM sactisynthase. This structure confers to the Ruminococcin C1 important clinical properties including stability to digestive conditions and physicochemical treatments, a higher affinity for bacteria than simulated intestinal epithelium, a valuable activity at therapeutic doses on a range of clinical pathogens, mediated by energy resources disruption, and finally safety for human gut tissues.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Clostridiales/química , Péptidos/química , Péptidos/farmacología , Antibacterianos/aislamiento & purificación , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Péptidos/aislamiento & purificaciónRESUMEN
Cyclopeptide alkaloids are an abundant class of plant cyclopeptides with over 200 analogs described and bioactivities ranging from analgesic to antiviral. While these natural products have been known for decades, their biosynthetic basis remains unclear. Using a transcriptome-mining approach, we link the cyclopeptide alkaloids from Ceanothus americanus to dedicated RiPP precursor peptides and identify new, widely distributed split BURP peptide cyclase containing gene clusters. Guided by our bioinformatic analysis, we identify and isolate new cyclopeptides from Coffea arabica, which we named arabipeptins. Reconstitution of the enzyme activity for the BURP found in the biosynthesis of arabipeptin A validates the activity of the newly discovered split BURP peptide cyclases. These results expand our understanding of the biosynthetic pathways responsible for diverse cyclic plant peptides and suggest that these side chain cross-link modifications are widely distributed in eudicots.
Asunto(s)
Productos Biológicos , Péptidos Cíclicos , Péptidos Cíclicos/metabolismo , Péptidos/química , Biología Computacional , Procesamiento Proteico-Postraduccional , Productos Biológicos/química , Vías Biosintéticas/genéticaRESUMEN
Aromatic prenyltransferases from cyanobactin biosynthetic pathways catalyse the chemoselective and regioselective intramolecular transfer of prenyl/geranyl groups from isoprene donors to an electron-rich position in these macrocyclic and linear peptides. These enzymes often demonstrate relaxed substrate specificity and are considered useful biocatalysts for structural diversification of peptides. Herein, we assess the isoprene donor specificity of the N1-tryptophan prenyltransferase AcyF from the anacyclamide A8P pathway using a library of 22 synthetic alkyl pyrophosphate analogues, of which many display reactive groups that are amenable to additional functionalization. We further used AcyF to introduce a reactive moiety into a tryptophan-containing cyclic peptide and subsequently used click chemistry to fluorescently label the enzymatically modified peptide. This chemoenzymatic strategy allows late-stage modification of peptides and is useful for many applications.
Asunto(s)
Dimetilaliltranstransferasa , Triptófano , Triptófano/química , Péptidos , Péptidos Cíclicos/química , Butadienos , Hemiterpenos , Dimetilaliltranstransferasa/metabolismo , Especificidad por SustratoRESUMEN
LanD flavoproteins catalyze oxidative decarboxylation of the C-terminal Cys residue of a peptide to produce an enethiol. This enethiol is highly reactive and can be coupled with an upstream dehydroamino acid through Michael addition to form S-[2-aminovinyl](3-methyl)cysteine, an unsaturated thioether residue known to be characteristic of an array of C-terminally macrocyclized, ribosomally synthesized and posttranslationally modified peptides (RiPPs). Based on a two-stage bioinformatics mining of posttranslational modifications (PTMs) related to C-terminal Cys processing, we report herein that LanD activity can couple with radical S-adenosylmethionine chemistry to provide a new unsaturated thioether residue, S-[2-aminovinyl]-3-carbamoylcysteine, by conjugating the resultant enethiol with Cß of the Asn residue in the C-terminal NxxC motif of a peptide for macrocyclization. This study furthers our understanding of the variety of PTMs involved in creating the structure diversity of macrocyclic RiPPs.
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Flavoproteínas , Sulfuros , Secuencia de Aminoácidos , Sulfuros/química , Flavoproteínas/metabolismo , Péptidos/química , Oxidación-Reducción , Procesamiento Proteico-PostraduccionalRESUMEN
Lanthipeptides are ribosomally-synthesized natural products from bacteria featuring stable thioether-crosslinks and various bioactivities. Herein, we report on a new clade of tricyclic class-IV lanthipeptides with curvocidin from Thermomonospora curvata as its first representative. We obtained crystal structures of the corresponding lanthipeptide synthetase CuvL that showed a circular arrangement of its kinase, lyase and cyclase domains, forming a central reaction chamber for the iterative substrate processing involving nine catalytic steps. The combination of experimental data and artificial intelligence-based structural models identified the N-terminal subdomain of the kinase domain as the primary site of substrate recruitment. The ribosomal precursor peptide of curvocidin employs an amphipathic α-helix in its leader region as an anchor to CuvL, while its substrate core shuttles within the central reaction chamber. Our study thus reveals general principles of domain organization and substrate recruitment of class-IV and class-III lanthipeptide synthetases.
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Inteligencia Artificial , Ligasas , Ligasas/química , Péptidos/químicaRESUMEN
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a fascinating group of natural products that exhibit diverse structural features and bioactivities. P450-catalyzed RiPPs stand out as a unique but underexplored family. Herein, we introduce a rule-based genome mining strategy that harnesses the intrinsic biosynthetic principles of RiPPs, including the co-occurrence and co-conservation of precursors and P450s and interactions between them, successfully facilitating the identification of diverse P450-catalyzed RiPPs. Intensive BGC characterization revealed four new P450s, KstB, ScnB, MciB, and SgrB, that can catalyze the formation of Trp-Trp-Tyr (one C-C and two C-N bonds), Tyr-Trp (C-C bond), Trp-Trp (C-N bond), and His-His (ether bond) crosslinks, respectively, within three or four residues. KstB, ScnB, and MciB could accept non-native precursors, suggesting they could be promising starting templates for bioengineering to construct macrocycles. Our study highlights the potential of P450s to expand the chemical diversity of strained macrocyclic peptides and the range of biocatalytic tools available for peptide macrocyclization.
Asunto(s)
Productos Biológicos , Péptidos , Péptidos/química , Ribosomas/metabolismo , Bacterias/metabolismo , Genoma , Sistema Enzimático del Citocromo P-450/metabolismo , Procesamiento Proteico-Postraduccional , Productos Biológicos/químicaRESUMEN
Cihunamidesâ A-D (1-4), novel antibacterial RiPPs, were isolated from volcanic-island-derived Streptomyces sp. The structures of 1-4 were elucidated by 1 H, 13 C, and 15 N NMR, MS, and chemical derivatization; they contain a tetrapeptide core composed of WNIW, cyclized by a unique C-N linkage between two Trp units. Genome mining of the producer strain revealed two biosynthetic genes encoding a cytochromeâ P450 enzyme and a precursor peptide. Heterologous co-expression of the core genes demonstrated the biosynthesis of cihunamides through P450-mediated oxidative Trp-Trp cross-linking. Further bioinformatic analysis uncovered 252 homologous gene clusters, including that of tryptorubins, which possess a distinct Trp-Trp linkage. Cihunamides do not display the non-canonical atropisomerism shown in tryptorubins, which are the founding members of the "atropitide" family. Therefore, we propose to use a new RiPP family name, "bitryptides", for cihunamides, tryptorubins, and their congeners, wherein the Trp-Trp linkages define the structural class rather than non-canonical atropisomerism.
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Productos Biológicos , Péptidos , Péptidos/química , Biología Computacional , Procesamiento Proteico-Postraduccional , Genoma , Sistema Enzimático del Citocromo P-450/genéticaRESUMEN
BACKGROUND: Biocontrol agents are sustainable eco-friendly alternatives for chemical pesticides that cause adverse effects in the environment and toxicity in animals including humans. An improved understanding of the phyllosphere microbiology is of vital importance for biocontrol development. Most studies have been directed towards beneficial plant-microbe interactions and ignore the pathogens that might affect humans when consuming vegetables. In this study we extended this perspective and investigated potential biocontrol strains isolated from tomato and lettuce phyllosphere that can promote plant growth and potentially antagonize human pathogens as well as plant pathogens. Subsequently, we mined into their genomes for discovery of antimicrobial biosynthetic gene clusters (BGCs), that will be further characterized. RESULTS: The antimicrobial activity of 69 newly isolated strains from a healthy tomato and lettuce phyllosphere against several plant and human pathogens was screened. Three strains with the highest antimicrobial activity were selected and characterized (Bacillus subtilis STRP31, Bacillus velezensis SPL51, and Paenibacillus sp. PL91). All three strains showed a plant growth promotion effect on tomato and lettuce. In addition, genome mining of the selected isolates showed the presence of a large variety of biosynthetic gene clusters. A total of 35 BGCs were identified, of which several are already known, but also some putative novel ones were identified. Further analysis revealed that among the novel BGCs, one previously unidentified NRPS and two bacteriocins are encoded, the gene clusters of which were analyzed in more depth. CONCLUSIONS: Three recently isolated strains of the Bacillus genus were identified that have high antagonistic activity against lettuce and tomato plant pathogens. Known and unknown antimicrobial BGCs were identified in these antagonistic bacterial isolates, indicating their potential to be used as biocontrol agents. Our study serves as a strong incentive for subsequent purification and characterization of novel antimicrobial compounds that are important for biocontrol.
Asunto(s)
Antiinfecciosos , Solanum lycopersicum , Bacterias/genética , Humanos , Lactuca/genética , Solanum lycopersicum/genética , Familia de MultigenesRESUMEN
Microviridins are a prominent family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) featuring characteristic lactone and lactam rings. Their unusual cage-like architecture renders them highly potent serine protease inhibitors of which individual variants specifically inhibit different types of proteases of pharmacological interest. While posttranslational modifications are key for the stability and bioactivity of RiPPs, additional attractive properties can be introduced by functional tags. To date - although highly desirable - no method has been reported to incorporate functional tags in microviridin scaffolds or the overarching class of graspetides. In this study, a chemoenzymatic inâ vitro platform is used to introduce functional tags in various microviridin variants yielding biotinylated, dansylated or propargylated congeners. This straightforward approach paves the way for customized protease inhibitors with built-in functionalities that can help to unravel the still elusive ecological roles and targets of this remarkable class of compounds and to foster applications based on protease inhibition.
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Péptidos , Inhibidores de Serina Proteinasa , Péptidos/química , Procesamiento Proteico-Postraduccional , Péptido Hidrolasas , Lactamas , LactonasRESUMEN
The emergence and re-emergence of viral epidemics and the risks of antiviral drug resistance are a serious threat to global public health. New options to supplement or replace currently used drugs for antiviral therapy are urgently needed. The research in the field of ribosomally synthesized and post-translationally modified peptides (RiPPs) has been booming in the last few decades, in particular in view of their strong antimicrobial activities and high stability. The RiPPs with antiviral activity, especially those against enveloped viruses, are now also gaining more interest. RiPPs have a number of advantages over small molecule drugs in terms of specificity and affinity for targets, and over protein-based drugs in terms of cellular penetrability, stability and size. Moreover, the great engineering potential of RiPPs provides an efficient way to optimize them as potent antiviral drugs candidates. These intrinsic advantages underscore the good therapeutic prospects of RiPPs in viral treatment. With the aim to highlight the underrated antiviral potential of RiPPs and explore their development as antiviral drugs, we review the current literature describing the antiviral activities and mechanisms of action of RiPPs, discussing the ongoing efforts to improve their antiviral potential and demonstrate their suitability as antiviral therapeutics. We propose that antiviral RiPPs may overcome the limits of peptide-based antiviral therapy, providing an innovative option for the treatment of viral disease.
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Antivirales/química , Antivirales/farmacología , Descubrimiento de Drogas , Péptidos/química , Péptidos/farmacología , Procesamiento Proteico-Postraduccional , Animales , Antivirales/administración & dosificación , Antivirales/metabolismo , Sistemas de Liberación de Medicamentos , Humanos , Péptidos/administración & dosificación , Péptidos/metabolismo , Ribosomas/metabolismo , Virosis/tratamiento farmacológico , Virus/efectos de los fármacosRESUMEN
Marine biodiversity is represented by an exceptional and ample array of intriguing natural product chemistries. Due to their extensive post-translational modifications, ribosomal peptides-also known as ribosomally synthesized and post-translationally modified peptides (RiPPs)-exemplify a widely diverse class of natural products, endowing a broad range of pharmaceutically and biotechnologically relevant properties for therapeutic or industrial applications. Most RiPPs are of bacterial origin, yet their marine derivatives have been quite rarely investigated. Given the rapid advancement engaged in a more powerful genomics approach, more biosynthetic gene clusters and pathways for these ribosomal peptides continue to be increasingly characterized. Moreover, the genome-mining approach in integration with synthetic biology techniques has markedly led to a revolution of RiPP natural product discovery. Therefore, this present short review article focuses on the recent discovery of RiPPs from marine bacteria based on genome mining and synthetic biology approaches during the past decade. Their biosynthetic studies are discussed herein, particularly the organization of targeted biosynthetic gene clusters linked to the encoded RiPPs with potential bioactivities.