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1.
RNA ; 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34353925

RESUMO

In bacteria, trans-translation is the major quality control system for rescuing stalled ribosomes. It is mediated by tmRNA, a hybrid RNA with properties of both a tRNA and a mRNA, and the small protein SmpB. Because trans-translation is absent in eukaryotes but necessary for bacterial fitness or survival, it is a promising target for the development of novel antibiotics. To facilitate screening of chemical libraries, various reliable in vitro and in vivo systems have been created for assessing trans-translational activity. However, the aim of the current work was to permit the safe and easy in vitro evaluation of trans-translation from pathogenic bacteria, which are obviously the ones we should be targeting. Based on green fluorescent protein (GFP) reassembly during active trans-translation, we have created a cell-free assay adapted to the rapid evaluation of trans-translation in ESKAPE bacteria, with 24 different possible combinations. It can be used for easy high-throughput screening of chemical compounds as well as for exploring the mechanism of trans-translation in these pathogens.

2.
Nat Commun ; 12(1): 4909, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389707

RESUMO

In bacteria, trans-translation is the main rescue system, freeing ribosomes stalled on defective messenger RNAs. This mechanism is driven by small protein B (SmpB) and transfer-messenger RNA (tmRNA), a hybrid RNA known to have both a tRNA-like and an mRNA-like domain. Here we present four cryo-EM structures of the ribosome during trans-translation at resolutions from 3.0 to 3.4 Å. These include the high-resolution structure of the whole pre-accommodated state, as well as structures of the accommodated state, the translocated state, and a translocation intermediate. Together, they shed light on the movements of the tmRNA-SmpB complex in the ribosome, from its delivery by the elongation factor EF-Tu to its passage through the ribosomal A and P sites after the opening of the B1 bridges. Additionally, we describe the interactions between the tmRNA-SmpB complex and the ribosome. These explain why the process does not interfere with canonical translation.


Assuntos
Proteínas de Escherichia coli/genética , Escherichia coli/genética , Biossíntese de Proteínas/genética , RNA Bacteriano/genética , Proteínas de Ligação a RNA/genética , Ribossomos/genética , Sítios de Ligação/genética , Microscopia Crioeletrônica , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Modelos Moleculares , Conformação de Ácido Nucleico , Ligação Proteica , Domínios Proteicos , RNA Bacteriano/química , RNA Bacteriano/metabolismo , RNA Mensageiro/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de Transferência/química , RNA de Transferência/genética , RNA de Transferência/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Ribossomos/metabolismo , Ribossomos/ultraestrutura
3.
EMBO Rep ; 22(5): e51412, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33710763

RESUMO

In the past decades, many studies reported the presence of endoplasmic reticulum (ER)-resident proteins in the cytosol. However, the mechanisms by which these proteins relocate and whether they exert cytosolic functions remain unknown. We find that a subset of ER luminal proteins accumulates in the cytosol of glioblastoma cells isolated from mouse and human tumors. In cultured cells, ER protein reflux to the cytosol occurs upon ER proteostasis perturbation. Using the ER luminal protein anterior gradient 2 (AGR2) as a proof of concept, we tested whether the refluxed proteins gain new functions in the cytosol. We find that refluxed, cytosolic AGR2 binds and inhibits the tumor suppressor p53. These data suggest that ER reflux constitutes an ER surveillance mechanism to relieve the ER from its contents upon stress, providing a selective advantage to tumor cells through gain-of-cytosolic functions-a phenomenon we name ER to Cytosol Signaling (ERCYS).


Assuntos
Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático , Animais , Citosol/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Camundongos , Proteínas/metabolismo
4.
BMC Microbiol ; 20(1): 237, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32746783

RESUMO

BACKGROUND: The increase in bacterial resistance phenotype cases is a global health problem. New strategies must be explored by the scientific community in order to create new treatment alternatives. Animal venoms are a good source for antimicrobial peptides (AMPs), which are excellent candidates for new antimicrobial drug development. Cathelicidin-related antimicrobial peptides (CRAMPs) from snake venoms have been studied as a model for the design of new antimicrobial pharmaceuticals against bacterial infections. RESULTS: In this study we present an 11 amino acid-long peptide, named pseudonajide, which is derived from a Pseudonaja textilis venom peptide and has antimicrobial and antibiofilm activity against Staphylococcus epidermidis. Pseudonajide was selected based on the sequence alignments of various snake venom peptides that displayed activity against bacteria. Antibiofilm activity assays with pseudonajide concentrations ranging from 3.12 to 100 µM showed that the lowest concentration to inhibit biofilm formation was 25 µM. Microscopy analysis demonstrated that pseudonajide interacts with the bacterial cell envelope, disrupting the cell walls and membranes, leading to morphological defects in prokaryotes. CONCLUSIONS: Our results suggest that pseudonajide's positives charges interact with negatively charged cell wall components of S. epidermidis, leading to cell damage and inhibiting biofilm formation.

5.
Nucleic Acids Res ; 48(4): e22, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31919515

RESUMO

In order to discover new antibiotics with improved activity and selectivity, we created a reliable in vitro reporter system to detect trans-translation activity, the main mechanism for recycling ribosomes stalled on problematic messenger RNA (mRNA) in bacteria. This system is based on an engineered tmRNA variant that reassembles the green fluorescent protein (GFP) when trans-translation is active. Our system is adapted for high-throughput screening of chemical compounds by fluorescence.


Assuntos
Bactérias/genética , Proteínas de Fluorescência Verde/genética , Biossíntese de Proteínas , RNA Mensageiro/genética , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Humanos , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas de Ligação a RNA/genética , Ribossomos/efeitos dos fármacos , Ribossomos/genética
6.
Int J Pharm ; 574: 118872, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31812797

RESUMO

Medical devices (indwelling) have greatly improved healthcare. Nevertheless, infections related to the use of these apparatuses continue to be a major clinical concern. Biofilms form on surfaces after bacterial adhesion, and they function as bacterial reservoirs and as resistance and tolerance factors against antibiotics and the host immune response. Technological strategies to control biofilms and bacterial adhesion, such as the use of surface coatings, are being explored more frequently, and natural peptides may promote their development. In this study, we purified and identified antibiofilm peptides from Capsicum baccatum (red pepper) using chromatography-tandem mass spectrometry, MALDI-MS, MS/MS and bioinformatics. These peptides strongly controlled biofilm formation by Staphylococcus epidermidis, the most prevalent pathogen in device-related infections, without any antibiotic activity. Furthermore, natural peptide-coated surfaces dislayed effective antiadhesive proprieties and showed no cytotoxic effects against different representative human cell lines. Finally, we determined the lead peptide predicted by Mascot and identified CSP37, which may be useful as a prime structure for the design of new antibiofilm agents. Together, these results shed light on natural Capsicum peptides as a possible antiadhesive coat to prevent medical device colonization.


Assuntos
Antibacterianos/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Capsicum/química , Peptídeos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus epidermidis/efeitos dos fármacos , Linhagem Celular Tumoral , Materiais Revestidos Biocompatíveis/química , Células HCT116 , Humanos , Células MCF-7 , Células PC-3 , Espectrometria de Massas em Tandem/métodos
7.
Bioorg Med Chem ; 27(21): 115097, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31540826

RESUMO

The reality and intensity of antibiotic resistance in pathogenic bacteria calls for the rapid development of new antimicrobial drugs. In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. Because trans-translation is absent in eukaryotes but necessary to avoid ribosomal stalling and therefore essential for bacterial survival, it is a promising target either for novel antibiotics or for improving the activities of the protein synthesis inhibitors already in use. Oxadiazole derivatives display strong bactericidal activity against a large number of bacteria, but their effects on trans-translation were recently questioned. In this work, a series of new 1,3,4-oxadiazole derivatives and analogs were synthesized and assessed for their efficiency as antimicrobial agents against a wide range of gram-positive and gram-negative pathogenic strains. Despite the strong antimicrobial activity observed in these molecules, it turns out that they do not target trans-translation in vivo, but they definitely act on other cellular pathways.


Assuntos
Antibacterianos/farmacologia , Oxidiazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Sinergismo Farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Oxidiazóis/síntese química , Oxidiazóis/toxicidade
8.
Ann N Y Acad Sci ; 1447(1): 80-87, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30815901

RESUMO

In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. This key process is universally conserved and plays a crucial role in the viability and virulence of all bacteria. It is performed by transfer-messenger RNA (tmRNA) and its protein partner small protein B (SmpB). Here, we show that tmRNA is a key molecule that could have given birth to modern protein synthesis. The traces of an ancient RNA world persist in the structure of modern tmRNA, suggesting its old origins. Therefore, since it has both tRNA and mRNA functions, tmRNA could be the missing link that allowed modern genetic code to be read by the ribosome.


Assuntos
Biossíntese de Proteínas/fisiologia , RNA Bacteriano/genética , RNA Mensageiro/genética , RNA de Transferência/genética , Animais , Humanos , Estrutura Secundária de Proteína , RNA Bacteriano/química , RNA Mensageiro/química , RNA de Transferência/química
9.
Nat Commun ; 10(1): 752, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30765709

RESUMO

Viruses modulate ecosystems by directly altering host metabolisms through auxiliary metabolic genes. However, viral genomes are not known to encode the core components of translation machinery, such as ribosomal proteins (RPs). Here, using reference genomes and global-scale viral metagenomic datasets, we identify 14 different RPs across viral genomes arising from cultivated viral isolates and metagenome-assembled viruses. Viruses tend to encode dynamic RPs, easily exchangeable between ribosomes, suggesting these proteins can replace cellular versions in host ribosomes. Functional assays confirm that the two most common virus-encoded RPs, bS21 and bL12, are incorporated into 70S ribosomes when expressed in Escherichia coli. Ecological distribution of virus-encoded RPs suggests some level of ecosystem adaptations as aquatic viruses and viruses of animal-associated bacteria are enriched for different subsets of RPs. Finally, RP genes are under purifying selection and thus likely retained an important function after being horizontally transferred into virus genomes.

10.
Trends Biochem Sci ; 43(12): 938-950, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30337135

RESUMO

Great progress has been made toward solving the atomic structure of the ribosome, which is the main biosynthetic machine in cells, but we still do not have a full picture of exactly how cellular ribosomes function. Based on the analysis of crystallographic and electron microscopy data, we propose a basic model of the structural organization of ribosomes into a compartment. This compartment is regularly formed by arrays of ribosomal tetramers made up of two dimers that are actually facing in opposite directions. The compartment functions as the main 'factory' for the production of cellular proteins. The model is consistent with the existing biochemical and genetic data. We also consider the functional connections of such a compartment with cellular transcription and ribosomal biogenesis.


Assuntos
Ribossomos/metabolismo , RNA Polimerases Dirigidas por DNA/metabolismo , Microscopia Eletrônica , Polirribossomos/genética , Polirribossomos/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo
11.
Front Microbiol ; 9: 2157, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271394

RESUMO

Pathogenic biofilms are a global health care concern, as they can cause extensive antibiotic resistance, morbidity, mortality, and thereby substantial economic loss. Scientific efforts have been made over the past few decades, but so far there is no effective treatment targeting the bacteria in biofilms. Antimicrobial peptidomimetics have been proposed as promising potential anti-biofilm agents. Indeed, these structurally enhanced molecules can mimic the action of peptides but are not susceptible to proteolysis or immunogenicity, the characteristic limitations of natural peptides. Here, we provide insights into antibiofilm peptidomimetic strategies and molecular targets, and discuss the design of two major peptidomimetics classes: AApeptides (N-acylated-N-aminoethyl-substituted peptides) and peptoids (N-substituted glycine units). In particular, we present details of their structural diversity and discuss the possible improvements that can be implemented in order to develop antibiofilm drug alternatives.

12.
Biochimie ; 151: 159-165, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29890204

RESUMO

The "Bioénergétique et Ingénierie des Protéines (BIP)" laboratory, CNRS (France), organized its first French workshop on molecular chaperone proteins and protein folding in November 2017. The goal of this workshop was to gather scientists working in France on chaperone proteins and protein folding. This initiative was a great success with excellent talks and fruitful discussions. The highlights were on the description of unexpected functions and post-translational regulation of known molecular chaperones (such as Hsp90, Hsp33, SecB, GroEL) and on state-of-the-art methods to tackle questions related to this theme, including Cryo-electron microscopy, Nuclear Magnetic Resonance (NMR), Electron Paramagnetic Resonance (EPR), simulation and modeling. We expect to organize a second workshop in two years that will include more scientists working in France in the chaperone field.


Assuntos
Chaperoninas/metabolismo , Biofísica , França
13.
Nucleic Acids Res ; 46(6): 3211-3217, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29408956

RESUMO

During translation's elongation cycle, elongation factor G (EF-G) promotes messenger and transfer RNA translocation through the ribosome. Until now, the structures reported for EF-G-ribosome complexes have been obtained by trapping EF-G in the ribosome. These results were based on use of non-hydrolyzable guanosine 5'-triphosphate (GTP) analogs, specific inhibitors or a mutated EF-G form. Here, we present the first cryo-electron microscopy structure of EF-G bound to ribosome in the absence of an inhibitor. The structure reveals a natural conformation of EF-G·GDP in the ribosome, with a previously unseen conformation of its third domain. These data show how EF-G must affect translocation, and suggest the molecular mechanism by which fusidic acid antibiotic prevents the release of EF-G after GTP hydrolysis.


Assuntos
Proteínas de Bactérias/metabolismo , Fator G para Elongação de Peptídeos/metabolismo , Biossíntese de Proteínas , Ribossomos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/ultraestrutura , Microscopia Crioeletrônica , Guanosina Trifosfato/metabolismo , Hidrólise , Modelos Moleculares , Conformação Molecular , Fator G para Elongação de Peptídeos/química , Fator G para Elongação de Peptídeos/ultraestrutura , Ligação Proteica , Conformação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismo , Ribossomos/química , Ribossomos/ultraestrutura , Thermus thermophilus/metabolismo
14.
J Mol Biol ; 429(23): 3617-3625, 2017 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-29031699

RESUMO

In bacteria, trans-translation is the main quality control mechanism for rescuing ribosomes arrested during translation. This key process is universally conserved and plays a critical role in the viability and virulence of many pathogens. We developed a reliable in vivo double-fluorescence reporter system for the simultaneous quantification of both trans-translation and the associated proteolysis activities in bacteria. The assay was validated using mutant bacteria lacking tmRNA, SmpB, and the ClpP protease. Both antisense tmRNA-binding RNA and a peptide mimicking the SmpB C-terminal tail proved to be potent inhibitors of trans-translation in vivo. The double-fluorescent reporter was also tested with KKL-35, an oxadiazole derivative that is supposed to be a promising trans-translation inhibitor, and it surprisingly turns out that trans-translation is not the only target of KKL-35 in vivo.


Assuntos
Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Biossíntese de Proteínas , RNA Bacteriano/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribossomos/metabolismo , Proteínas de Bactérias/genética , RNA Bacteriano/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Ribossomos/genética
15.
Prion ; 11(2): 89-97, 2017 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-28362551

RESUMO

It is no longer necessary to demonstrate that ribosome is the central machinery of protein synthesis. But it is less known that it is also key player of the protein folding process through another conserved function: the protein folding activity of the ribosome (PFAR). This ribozyme activity, discovered more than 2 decades ago, depends upon the domain V of the large rRNA within the large subunit of the ribosome. Surprisingly, we discovered that anti-prion compounds are also potent PFAR inhibitors, highlighting an unexpected link between PFAR and prion propagation. In this review, we discuss the ancestral origin of PFAR in the light of the ancient RNA world hypothesis. We also consider how this ribosomal activity fits into the landscape of cellular protein chaperones involved in the appearance and propagation of prions and other amyloids in mammals. Finally, we examine how drugs targeting the protein folding activity of the ribosome could be active against mammalian prion and other protein aggregation-based diseases, making PFAR a promising therapeutic target for various human protein misfolding diseases.


Assuntos
Príons/metabolismo , Dobramento de Proteína , Ribossomos/metabolismo , Ribossomos/patologia , Animais , Proteínas de Choque Térmico/metabolismo , Humanos , Modelos Moleculares , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Príons/química , Biossíntese de Proteínas , RNA Ribossômico/metabolismo
16.
Methods ; 117: 59-66, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-27729294

RESUMO

Polysomes are macromolecular complexes made up of multiple ribosomes simultaneously translating a single mRNA into polypeptide chains. Together, the cellular mRNAs translated in this way are referred to 'translatome.' Translation determines a cell's overall gene expression profile. Studying translatome leads to a better understanding of the translational machinery and of its complex regulatory pathways. Given its fundamental role in cell homeostasis and division, bacterial translation is an important target for antibiotics. However, there are no detailed protocols for polysome purification from Staphylococcus aureus, the human pathogen responsible for the majority of multi-drug resistance issues. We therefore developed methods for the isolation of active polysomes, ribosomes, and ribosomal subunits, examining the purity and quality of each fraction and monitoring polysomal activity during protein synthesis. These steps are mandatory for the use of purified S. aureus polysomes and ribosomes for structural studies or for genome-scale analysis of most translated mRNAs.


Assuntos
Fracionamento Celular/métodos , Polirribossomos/química , Subunidades Ribossômicas Maiores de Bactérias/química , Subunidades Ribossômicas Menores de Bactérias/química , Staphylococcus aureus/genética , Eletroforese em Gel de Ágar , Microscopia Eletrônica , Polirribossomos/ultraestrutura , Biossíntese de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Subunidades Ribossômicas Maiores de Bactérias/ultraestrutura , Subunidades Ribossômicas Menores de Bactérias/ultraestrutura , Staphylococcus aureus/metabolismo
17.
Sci Rep ; 6: 32117, 2016 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-27633137

RESUMO

6AP and GA are potent inhibitors of yeast and mammalian prions and also specific inhibitors of PFAR, the protein-folding activity borne by domain V of the large rRNA of the large subunit of the ribosome. We therefore explored the link between PFAR and yeast prion [PSI(+)] using both PFAR-enriched mutants and site-directed methylation. We demonstrate that PFAR is involved in propagation and de novo formation of [PSI(+)]. PFAR and the yeast heat-shock protein Hsp104 partially compensate each other for [PSI(+)] propagation. Our data also provide insight into new functions for the ribosome in basal thermotolerance and heat-shocked protein refolding. PFAR is thus an evolutionarily conserved cell component implicated in the prion life cycle, and we propose that it could be a potential therapeutic target for human protein misfolding diseases.


Assuntos
Proteínas de Choque Térmico/metabolismo , Fatores de Terminação de Peptídeos/metabolismo , Príons/metabolismo , Dobramento de Proteína , Ribossomos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Guanabenzo/farmacologia , Proteínas de Choque Térmico/genética , Mutação , Fatores de Terminação de Peptídeos/genética , Fenantridinas/farmacologia , Príons/genética , Dobramento de Proteína/efeitos dos fármacos , RNA Ribossômico/metabolismo , Ribossomos/genética , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética
18.
Nucleic Acids Res ; 44(17): 8041-51, 2016 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-27484476

RESUMO

The RNA world hypothesis refers to the early period on earth in which RNA was central in assuring both genetic continuity and catalysis. The end of this era coincided with the development of the genetic code and protein synthesis, symbolized by the apparition of the first non-random messenger RNA (mRNA). Modern transfer-messenger RNA (tmRNA) is a unique hybrid molecule which has the properties of both mRNA and transfer RNA (tRNA). It acts as a key molecule during trans-translation, a major quality control pathway of modern bacterial protein synthesis. tmRNA shares many common characteristics with ancestral RNA. Here, we present a model in which proto-tmRNAs were the first molecules on earth to support non-random protein synthesis, explaining the emergence of early genetic code. In this way, proto-tmRNA could be the missing link between the first mRNA and tRNA molecules and modern ribosome-mediated protein synthesis.


Assuntos
Biossíntese de Proteínas , RNA Bacteriano/metabolismo , Código Genético , Modelos Biológicos , RNA Bacteriano/química , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Ribossomos/metabolismo
20.
Med Sci (Paris) ; 31(3): 282-90, 2015 Mar.
Artigo em Francês | MEDLINE | ID: mdl-25855282

RESUMO

Protein synthesis is accomplished through a process known as translation and is carried out by the ribosome, a large macromolecular complex found in every living organism. Given the huge amount of biological data that must be deciphered, it is not uncommon for ribosomes to regularly stall during the process of translation. Any disruption of this finely tuned process will jeopardize the viability of the cell. In bacteria, the main quality-control mechanism for rescuing ribosomes that undergo arrest during translation is trans-translation, which is performed by transfer-messenger RNA (tmRNA) in association with small protein B (SmPB). However, other rescue systems have been discovered recently, revealing a far more complicated network of factors dedicated to ribosome rescue. These discoveries make it possible to consider inhibition of these pathways as a very promising target for the discovery of new antibiotics.


Assuntos
Biossíntese de Proteínas , Ribossomos/fisiologia , Animais , Códon de Terminação/genética , Códon de Terminação/metabolismo , Humanos , Redes e Vias Metabólicas , Terapia de Alvo Molecular , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/uso terapêutico , Controle de Qualidade , RNA Mensageiro/metabolismo , Ribossomos/efeitos dos fármacos , Fatores de Tempo
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