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1.
Proc Natl Acad Sci U S A ; 119(46): e2210562119, 2022 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-36343224

RESUMEN

The development of chimeric antigen receptor (CAR) T cell therapy has become a critical milestone in modern oncotherapy. Despite the remarkable in vitro effectiveness, the problem of safety and efficacy of CAR T cell therapy against solid tumors is challenged by the lack of tumor-specific antigens required to avoid on-target off-tumor effects. Spatially separating the cytotoxic function of CAR T cells from tumor antigen recognition provided by protein mediators allows for the precise control of CAR T cell cytotoxicity. Here, the high affinity and capability of the bacterial toxin-antitoxin barnase-barstar system were adopted to guide CAR T cells to solid tumors. The complementary modules based on (1) ankyrin repeat (DARPin)-barnase proteins and (2) barstar-based CAR (BsCAR) were designed to provide switchable targeting to tumor cells. The alteration of the DARPin-barnase switches enabled the targeting of different tumor antigens with a single BsCAR. A gradual increase in cytokine release and tunable BsCAR T cell cytotoxicity was achieved by varying DARPin-barnase loads. Switchable BsCAR T cell therapy was able to eradicate the HER2+ ductal carcinoma in vivo. Guiding BsCAR T cells by DARPin-barnase switches provides a universal approach for a controlled multitargeted adoptive immunotherapy.


Asunto(s)
Neoplasias , Linfocitos T , Humanos , Receptores de Antígenos de Linfocitos T , Inmunoterapia Adoptiva , Neoplasias/metabolismo , Antígenos de Neoplasias
2.
Mol Ther Nucleic Acids ; 27: 211-226, 2022 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-34976439

RESUMEN

Antisense gapmer oligonucleotides containing phosphoryl guanidine (PG) groups, e.g., 1,3-dimethylimidazolidin-2-imine, at three to five internucleotidic positions adjacent to the 3' and 5' ends were prepared via the Staudinger chemistry, which is compatible with conditions of standard automated solid-phase phosphoramidite synthesis for phosphodiester and, notably, phosphorothioate linkages, and allows one to design a variety of gapmeric structures with alternating linkages, and deoxyribose or 2'-O-methylribose backbone. PG modifications increased nuclease resistance in serum-containing medium for more than 21 days. Replacing two internucleotidic phosphates by PG groups in phosphorothioate-modified oligonucleotides did not decrease their cellular uptake in the absence of lipid carriers. Increasing the number of PG groups from two to seven per oligonucleotide reduced their ability to enter the cells in the carrier-free mode. Cationic liposomes provided similar delivery efficiency of both partially PG-modified and unmodified oligonucleotides. PG-gapmers were designed containing three to four PG groups at both wings and a central "window" of seven deoxynucleotides with either phosphodiester or phosphorothioate linkages targeted to MDR1 mRNA providing multiple drug resistance of tumor cells. Gapmers efficiently silenced MDR1 mRNA and restored the sensitivity of tumor cells to chemotherapeutics. Thus, PG-gapmers can be considered as novel, promising types of antisense oligonucleotides for targeting biologically relevant RNAs.

3.
Acta Naturae ; 13(3): 101-105, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34707901

RESUMEN

Modified nucleotides, including phosphoramidates and mesyl nucleotides, are very effective in inactivating gene expression in bacteria. Gyr A is the target gene in several organisms, including Plasmodium falciparum. Antisense reactions with bacteria infecting citrus plants are promising but incomplete. Human tissue culture cells assayed with a different target are also susceptible to the presence of mesyl oligonucleotides.

4.
Proc Natl Acad Sci U S A ; 117(51): 32370-32379, 2020 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-33288723

RESUMEN

The design of modified oligonucleotides that combine in one molecule several therapeutically beneficial properties still poses a major challenge. Recently a new type of modified mesyl phosphoramidate (or µ-) oligonucleotide was described that demonstrates high affinity to RNA, exceptional nuclease resistance, efficient recruitment of RNase H, and potent inhibition of key carcinogenesis processes in vitro. Herein, using a xenograft mouse tumor model, it was demonstrated that microRNA miR-21-targeted µ-oligonucleotides administered in complex with folate-containing liposomes dramatically inhibit primary tumor growth via long-term down-regulation of miR-21 in tumors and increase in biosynthesis of miR-21-regulated tumor suppressor proteins. This antitumoral effect is superior to the effect of the corresponding phosphorothioate. Peritumoral administration of µ-oligonucleotide results in its rapid distribution and efficient accumulation in the tumor. Blood biochemistry and morphometric studies of internal organs revealed no pronounced toxicity of µ-oligonucleotides. This new oligonucleotide class provides a powerful tool for antisense technology.


Asunto(s)
Amidas/química , Antineoplásicos/farmacología , MicroARNs/genética , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/farmacología , Ácidos Fosfóricos/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Masculino , Melanoma/genética , Melanoma/patología , Ratones SCID , Terapia Molecular Dirigida , Oligonucleótidos Antisentido/farmacocinética , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Proc Natl Acad Sci U S A ; 117(44): 27300-27306, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33087570

RESUMEN

Conventional "bulk" PCR often yields inefficient and nonuniform amplification of complex templates in DNA libraries, introducing unwanted biases. Amplification of single DNA molecules encapsulated in a myriad of emulsion droplets (emulsion PCR, ePCR) allows the mitigation of this problem. Different ePCR regimes were experimentally analyzed to identify the most robust techniques for enhanced amplification of DNA libraries. A phenomenological mathematical model that forms an essential basis for optimal use of ePCR for library amplification was developed. A detailed description by high-throughput sequencing of amplified DNA-encoded libraries highlights the principal advantages of ePCR over bulk PCR. ePCR outperforms PCR, reduces gross DNA errors, and provides a more uniform distribution of the amplified sequences. The quasi single-molecule amplification achieved via ePCR represents the fundamental requirement in case of complex DNA templates being prone to diversity degeneration and provides a way to preserve the quality of DNA libraries.


Asunto(s)
Emulsiones/química , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Reacción en Cadena de la Polimerasa/métodos , ADN/genética , Cartilla de ADN/genética , Biblioteca de Genes , Genoma/genética , Humanos , Modelos Teóricos , Técnicas de Amplificación de Ácido Nucleico/métodos , Moldes Genéticos
6.
Sci Adv ; 6(26): eaaz9861, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32637600

RESUMEN

Microbial communities are self-controlled by repertoires of lethal agents, the antibiotics. In their turn, these antibiotics are regulated by bioscavengers that are selected in the course of evolution. Kinase-mediated phosphorylation represents one of the general strategies for the emergence of antibiotic resistance. A new subfamily of AmiN-like kinases, isolated from the Siberian bear microbiome, inactivates antibiotic amicoumacin by phosphorylation. The nanomolar substrate affinity defines AmiN as a phosphotransferase with a unique catalytic efficiency proximal to the diffusion limit. Crystallographic analysis and multiscale simulations revealed a catalytically perfect mechanism providing phosphorylation exclusively in the case of a closed active site that counteracts substrate promiscuity. AmiN kinase is a member of the previously unknown subfamily representing the first evidence of a specialized phosphotransferase bioscavenger.

7.
Pest Manag Sci ; 76(9): 3217-3224, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32358830

RESUMEN

BACKGROUND: 'Candidatus Liberibacter asiaticus' (CLas) is the causal agent of the devastating citrus disease Huanglongbing (HLB) and is transmitted by the insect vector Diaphorina citri (Hemiptera: Liviidae). A potential approach for treating CLas infection is the use of synthetic nucleic acid-like oligomers to silence bacterial gene expression. Peptide conjugated morpholinos (PPMOs) targeting essential genes in CLas and the psyllid vector's endosymbiotic bacteria, Wolbachia (-Diaphorina, wDi), were evaluated using in vitro and in vivo assays. RESULTS: Expression of the wDi gyrA gene was significantly reduced following incubation of wDi cells with PPMOs. In addition, the viability of isolated wDi cells was greatly reduced when treated with PPMOs as compared to untreated cells. Feeding D. citri adults with a complementary PPMO (CLgyrA-14) showed significantly reduced (70% lower) expression of the CLas gyrA gene. CLas relative density was significantly lower in the psyllids fed with CLgyrA-14, when compared to untreated insects. Psyllids that were treated with CLgyrA-14 were less successful in transmitting the pathogen into uninfected plants, compared to untreated insects. CONCLUSION: The expression of essential genes in the D. citri symbiont, wDi and the HLB pathogen were suppressed in response to PPMO treatments. This study demonstrates the potential of PPMOs as a novel strategy for management of bacterial pathogens of fruit trees, such as HLB. © 2020 Society of Chemical Industry.


Asunto(s)
Citrus , Hemípteros , Rhizobiaceae , Animales , Morfolinos , Péptidos , Enfermedades de las Plantas , Rhizobiaceae/genética
8.
Front Pharmacol ; 10: 813, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31379580

RESUMEN

Novel alternatives to traditional antibiotics are now of great demand for the successful treatment of microbial infections. Here, we present the engineering and properties of new oligonucleotide inhibitors of RNase P, an essential bacterial enzyme. The series of 2'-O-methyl RNA (2'-OMe-RNA) and phosphoryl guanidine oligonucleotides were targeted to the substrate-binding region of M1 RNA subunit of the RNase P. Uniformly modified 2'-OMe RNA and selectively modified phosphoryl guanidine oligonucleotides possessed good stability in biological media and effectively inhibited RNase P. Their conjugates with transporting peptides were shown to penetrate bacterial cells (Escherichia coli and Acinetobacter baumannii) and inhibit bacterial growth.

9.
Proc Natl Acad Sci U S A ; 115(38): 9551-9556, 2018 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-30181282

RESUMEN

Microbiome spectra serve as critical clues to elucidate the evolutionary biology pathways, potential pathologies, and even behavioral patterns of the host organisms. Furthermore, exotic sources of microbiota represent an unexplored niche to discover microbial secondary metabolites. However, establishing the bacterial functionality is complicated by an intricate web of interactions inside the microbiome. Here we apply an ultrahigh-throughput (uHT) microfluidic droplet platform for activity profiling of the entire oral microbial community of the Siberian bear to isolate Bacillus strains demonstrating antimicrobial activity against Staphylococcus aureus Genome mining allowed us to identify antibiotic amicoumacin A (Ami) as responsible for inhibiting the growth of S. aureus Proteomics and metabolomics revealed a unique mechanism of Bacillus self-resistance to Ami, based on a subtle equilibrium of its deactivation and activation by kinase AmiN and phosphatase AmiO, respectively. We developed uHT quantitative single-cell analysis to estimate antibiotic efficacy toward different microbiomes and used it to determine the activity spectra of Ami toward human and Siberian bear microbiota. Thus, uHT microfluidic droplet platform activity profiling is a powerful tool for discovering antibiotics and quantifying external influences on a microbiome.


Asunto(s)
Antibacterianos/farmacología , Cumarinas/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento/métodos , Metabolómica/métodos , Animales , Antibacterianos/metabolismo , Bacillus pumilus/efectos de los fármacos , Bacillus pumilus/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Cumarinas/metabolismo , ADN Bacteriano/genética , ADN Bacteriano/aislamiento & purificación , Farmacorresistencia Bacteriana/fisiología , Microbioma Gastrointestinal/fisiología , Perfilación de la Expresión Génica , Voluntarios Sanos , Humanos , Dispositivos Laboratorio en un Chip , Proteómica/métodos , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido Nucleico , Análisis de la Célula Individual/métodos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , Ursidae/microbiología
10.
Proc Natl Acad Sci U S A ; 114(10): 2550-2555, 2017 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-28202731

RESUMEN

Ultrahigh-throughput screening (uHTS) techniques can identify unique functionality from millions of variants. To mimic the natural selection mechanisms that occur by compartmentalization in vivo, we developed a technique based on single-cell encapsulation in droplets of a monodisperse microfluidic double water-in-oil-in-water emulsion (MDE). Biocompatible MDE enables in-droplet cultivation of different living species. The combination of droplet-generating machinery with FACS followed by next-generation sequencing and liquid chromatography-mass spectrometry analysis of the secretomes of encapsulated organisms yielded detailed genotype/phenotype descriptions. This platform was probed with uHTS for biocatalysts anchored to yeast with enrichment close to the theoretically calculated limit and cell-to-cell interactions. MDE-FACS allowed the identification of human butyrylcholinesterase mutants that undergo self-reactivation after inhibition by the organophosphorus agent paraoxon. The versatility of the platform allowed the identification of bacteria, including slow-growing oral microbiota species that suppress the growth of a common pathogen, Staphylococcus aureus, and predicted which genera were associated with inhibitory activity.


Asunto(s)
Butirilcolinesterasa/química , Ensayos Analíticos de Alto Rendimiento/instrumentación , Técnicas Analíticas Microfluídicas/métodos , Paraoxon/química , Análisis de la Célula Individual/instrumentación , Antibiosis , Biodiversidad , Comunicación Celular , Emulsiones , Citometría de Flujo , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Técnicas Analíticas Microfluídicas/instrumentación , Aceites Volátiles/química , Fenotipo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Agua/química
11.
Sci Rep ; 6: 26950, 2016 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-27230692

RESUMEN

Metallic alloys are normally composed of multiple constituent elements in order to achieve integration of a plurality of properties required in technological applications. However, conventional alloy development paradigm, by sequential trial-and-error approach, requires completely unrelated strategies to optimize compositions out of a vast phase space, making alloy development time consuming and labor intensive. Here, we challenge the conventional paradigm by proposing a combinatorial strategy that enables parallel screening of a multitude of alloys. Utilizing a typical metallic glass forming alloy system Zr-Cu-Al-Ag as an example, we demonstrate how glass formation and antibacterial activity, two unrelated properties, can be simultaneously characterized and the optimal composition can be efficiently identified. We found that in the Zr-Cu-Al-Ag alloy system fully glassy phase can be obtained in a wide compositional range by co-sputtering, and antibacterial activity is strongly dependent on alloy compositions. Our results indicate that antibacterial activity is sensitive to Cu and Ag while essentially remains unchanged within a wide range of Zr and Al. The proposed strategy not only facilitates development of high-performing alloys, but also provides a tool to unveil the composition dependence of properties in a highly parallel fashion, which helps the development of new materials by design.


Asunto(s)
Aleaciones/química , Aluminio/química , Antibacterianos/química , Técnicas Químicas Combinatorias , Plata/química , Aleaciones/farmacología , Antibacterianos/farmacología , Cobre/química , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Escherichia coli/ultraestructura , Vidrio/química , Microscopía de Fuerza Atómica , Relación Estructura-Actividad , Circonio/química
12.
Crit Rev Microbiol ; 42(6): 847-65, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26258445

RESUMEN

An important current issue of modern molecular medicine and biotechnology is the search for new approaches to early diagnostic assays and adequate therapy of infectious diseases. One of the promising solutions to this problem might be a development of nucleic acid aptamers capable of interacting specifically with bacteria, protozoa, and viruses. Such aptamers can be used for the specific recognition of infectious agents as well as for blocking of their functions. The present review summarizes various modern SELEX techniques used in this field, and of several currently identified aptamers against viral particles and unicellular organisms, and their applications. The prospects of applying nucleic acid aptamers for the development of novel detection systems and antibacterial and antiviral drugs are discussed.


Asunto(s)
Aptámeros de Nucleótidos/farmacología , Bacterias/efectos de los fármacos , Enfermedades Transmisibles/microbiología , Enfermedades Transmisibles/virología , Virus/efectos de los fármacos , Animales , Bacterias/genética , Bacterias/metabolismo , Humanos , Técnica SELEX de Producción de Aptámeros/métodos , Virus/genética , Virus/metabolismo
13.
Proc Natl Acad Sci U S A ; 112(38): 11935-40, 2015 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-26351679

RESUMEN

Identification and genetic validation of new targets from available genome sequences are critical steps toward the development of new potent and selective antimalarials. However, no methods are currently available for large-scale functional analysis of the Plasmodium falciparum genome. Here we present evidence for successful use of morpholino oligomers (MO) to mediate degradation of target mRNAs or to inhibit RNA splicing or translation of several genes of P. falciparum involved in chloroquine transport, apicoplast biogenesis, and phospholipid biosynthesis. Consistent with their role in the parasite life cycle, down-regulation of these essential genes resulted in inhibition of parasite development. We show that a MO conjugate that targets the chloroquine-resistant transporter PfCRT is effective against chloroquine-sensitive and -resistant parasites, causes enlarged digestive vacuoles, and renders chloroquine-resistant strains more sensitive to chloroquine. Similarly, we show that a MO conjugate that targets the PfDXR involved in apicoplast biogenesis inhibits parasite growth and that this defect can be rescued by addition of isopentenyl pyrophosphate. MO-based gene regulation is a viable alternative approach to functional analysis of the P. falciparum genome.


Asunto(s)
Morfolinos/farmacología , Plasmodium falciparum/genética , Biosíntesis de Proteínas/efectos de los fármacos , Proteolisis/efectos de los fármacos , Empalme del ARN/efectos de los fármacos , Animales , Antimaláricos/farmacología , Artemisininas/farmacología , Cloroquina/farmacología , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Medicamentos/efectos de los fármacos , Citometría de Flujo , Genes Reporteros , Hemiterpenos/metabolismo , Luciferasas/metabolismo , Compuestos Organofosforados/metabolismo , Parásitos/efectos de los fármacos , Parásitos/genética , Parásitos/crecimiento & desarrollo , Péptidos/farmacología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrollo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Secuencia de ADN
14.
Nucleic Acids Res ; 43(11): 5442-50, 2015 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-25953854

RESUMEN

Human RNase P is implicated in transcription of small non-coding RNA genes by RNA polymerase III (Pol III), but the precise role of this ribonucleoprotein therein remains unknown. We here show that targeted destruction of HeLa nuclear RNase P inhibits transcription of 5S rRNA genes in whole cell extracts, if this precedes the stage of initiation complex formation. Biochemical purification analyses further reveal that this ribonucleoprotein is recruited to 5S rRNA genes as a part of proficient initiation complexes and the activity persists at reinitiation. Knockdown of RNase P abolishes the assembly of initiation complexes by preventing the formation of the initiation sub-complex of Pol III. Our results demonstrate that the structural intactness, but not the endoribonucleolytic activity per se, of RNase P is critical for the function of Pol III in cells and in extracts.


Asunto(s)
ARN Polimerasa III/metabolismo , ARN Ribosómico 5S/genética , Ribonucleasa P/metabolismo , Iniciación de la Transcripción Genética , Células HeLa , Humanos , ARN no Traducido/metabolismo , Ribonucleasa P/antagonistas & inhibidores , Ribonucleasa P/aislamiento & purificación
15.
RNA ; 21(4): 513-4, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25780119
16.
J Biol Chem ; 288(28): 20558-67, 2013 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-23729665

RESUMEN

The human malaria parasite Plasmodium falciparum is absolutely dependent on the acquisition of host pantothenate for its development within human erythrocytes. Although the biochemical properties of this transport have been characterized, the molecular identity of the parasite-encoded pantothenate transporter remains unknown. Here we report the identification and functional characterization of the first protozoan pantothenate transporter, PfPAT, from P. falciparum. We show using cell biological, biochemical, and genetic analyses that this transporter is localized to the parasite plasma membrane and plays an essential role in parasite intraerythrocytic development. We have targeted PfPAT to the yeast plasma membrane and showed that the transporter complements the growth defect of the yeast fen2Δ pantothenate transporter-deficient mutant and mediates the entry of the fungicide drug, fenpropimorph. Our studies in P. falciparum revealed that fenpropimorph inhibits the intraerythrocytic development of both chloroquine- and pyrimethamine-resistant P. falciparum strains with potency equal or better than that of currently available pantothenate analogs. The essential function of PfPAT and its ability to deliver both pantothenate and fenpropimorph makes it an attractive target for the development and delivery of new classes of antimalarial drugs.


Asunto(s)
Membrana Celular/metabolismo , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/metabolismo , Simportadores/metabolismo , Secuencia de Aminoácidos , Animales , Antimaláricos/farmacología , Cloroquina/farmacología , Resistencia a Medicamentos/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Eritrocitos/ultraestructura , Prueba de Complementación Genética , Células HEK293 , Interacciones Huésped-Parásitos/efectos de los fármacos , Humanos , Malaria Falciparum/parasitología , Microscopía Fluorescente , Microscopía Inmunoelectrónica , Datos de Secuencia Molecular , Morfolinas/metabolismo , Morfolinas/farmacología , Mutación , Ácido Pantoténico/metabolismo , Ácido Pantoténico/farmacología , Filogenia , Plasmodium falciparum/genética , Plasmodium falciparum/fisiología , Proteínas Protozoarias/genética , Pirimetamina/farmacología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Homología de Secuencia de Aminoácido , Simportadores/clasificación , Simportadores/genética
17.
Int J Pharm ; 453(2): 651-5, 2013 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-23727592

RESUMEN

Management of skin wound infections presents a serious problem in the clinic, in the community, and in both civilian and military clinical treatment centers. Staphylococcus aureus is one of the most common microbial pathogens in cutaneous wounds. Peptide-morpholino oligomer (PMO) conjugates targeted to S. aureus gyrase A mRNA have shown the ability to reduce bacterial viability by direct site-specific mRNA cleavage via RNase P. As a treatment, these conjugates have the added advantages of not being susceptible to resistance due to genetic mutations and are effective against drug resistant strains. While this strategy has proven effective in liquid culture, it has yet to be evaluated in an animal model of infected surface wounds. In the present study, we combined PMO conjugates with a thermoresponsive gel delivery system to treat full-thickness mouse cutaneous wounds infected with S. aureus. Wounds treated with a single dose of PMO conjugate displayed improved healing that was associated with increased epithelialization, reduced bacterial load, and increased matrix deposition. Taken together, our findings demonstrate the efficacy and flexibility of the PMO conjugate drug delivery system and make it an attractive and novel topical antimicrobial agent.


Asunto(s)
Antibacterianos/administración & dosificación , Girasa de ADN/genética , Morfolinos/administración & dosificación , Péptidos/administración & dosificación , Staphylococcus aureus , Infección de Heridas/terapia , Animales , Sistemas de Liberación de Medicamentos , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/genética , Piel/patología , Cicatrización de Heridas/efectos de los fármacos , Infección de Heridas/patología
18.
Proc Natl Acad Sci U S A ; 110(21): 8686-9, 2013 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-23650357

RESUMEN

A cell-penetrating peptide (CPP)-morpholino oligonucleotide (MO) conjugate (PMO) that has an antibiotic effect in culture had some contaminating CPPs in earlier preparations. The mixed conjugate had gene-specific and gene-nonspecific effects. An improved purification procedure separates the PMO from the free CPP and MO. The gene-specific effects are a result of the PMO, and the nonspecific effects are a result of the unlinked, unreacted CPP. The PMO and the CPP can be mixed together, as has been shown previously in earlier experiments, and have a combined effect as an antibiotic. Kinetic analysis of these effects confirm this observation. The effect of the CPP is bacteriostatic. The effect of the PMO appears to be bacteriocidal. An assay for mutations that would alter the ability of these agents to affect bacterial viability is negative.


Asunto(s)
Antibacterianos , Bacterias/crecimiento & desarrollo , Péptidos de Penetración Celular , Morfolinos , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Péptidos de Penetración Celular/síntesis química , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacología , Morfolinos/síntesis química , Morfolinos/química , Morfolinos/farmacología
19.
RNA ; 19(5): 589-90, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23592800

RESUMEN

Following the naming of the RNA World for the hypothetical biochemical world during very early life forms, the current world was named the Protein World. However, the astonishing high level of transcripts from virtually all chromosomes in an organism now found in eucaryotes, as well as their extensive roles in regulating gene expression, suggests that today's world should be labeled as the RNA-Protein World.


Asunto(s)
Proteínas/genética , ARN/genética , Cromosomas/genética , Eucariontes/genética , Humanos
20.
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