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1.
Anticancer Res ; 39(11): 6145-6153, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704842

RESUMO

AIM: This study aimed to evaluate the antitumor effects of cyclolinopeptide (CL), which suppresses receptor activator of nuclear factor-κB ligand (RANKL) signalling on giant-cell tumours of the bone (GCTB) cells. MATERIALS AND METHODS: GCTB cell lines were established, and the inhibition of cell growth by CL was evaluated using the water-soluble tetrazolium salt-8 cell proliferation assay, cell cycle assay, and 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay. RANKL and runt-related transcription factor 2 (RUNX2) expression levels were evaluated using real-time polymerase chain reaction before and after CL administration. RESULTS: The dose-dependent inhibition of GCTB cells was significantly pronounced in the CL-administered group compared to the non-CL-administered group (p<0.05). In the CL-administered group, the ratio of cells in the G0/G1 phase was increased, but the ratio of EdU-positive cells was decreased (p<0.05). RANKL and RUNX2 levels were decreased in the CL-administered group (p<0.05). CONCLUSION: CL has antitumor effects on GCTB in vitro.


Assuntos
Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Tumor de Células Gigantes do Osso/patologia , Peptídeos Cíclicos/farmacologia , Células Estromais/patologia , Biomarcadores Tumorais/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Tumor de Células Gigantes do Osso/tratamento farmacológico , Tumor de Células Gigantes do Osso/genética , Tumor de Células Gigantes do Osso/metabolismo , Humanos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Tumorais Cultivadas
2.
Microbiol Res ; 229: 126329, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31518853

RESUMO

The genus Serratia is a predominantly unexplored source of antimicrobial secondary metabolites. The aim of the current study was thus to isolate and evaluate the antimicrobial properties of biosurfactants produced by Serratia species. Forty-nine (n = 34 pigmented; n = 15 non-pigmented) biosurfactant producing Serratia strains were isolated from environmental sources and selected isolates (n = 11 pigmented; n = 11 non-pigmented) were identified as Serratia marcescens using molecular typing. The swrW gene (serrawettin W1 synthetase) was detected in all the screened pigmented strains and one non-pigmented strain and primers were designed for the detection of the swrA gene (non-ribosomal serrawettin W2 synthetase), which was detected in nine non-pigmented strains. Crude extracts obtained from S. marcescens P1, NP1 and NP2 were chemically characterised using ultra-performance liquid chromatography coupled to electrospray ionisation mass spectrometry (UPLC-ESI-MS), which revealed that P1 produced serrawettin W1 homologues and prodigiosin, while NP1 produced serrawettin W1 homologues and glucosamine derivative A. In contrast, serrawettin W2 analogues were predominantly identified in the crude extract obtained from S. marcescens NP2. Both P1 and NP1 crude extracts displayed broad-spectrum antimicrobial activity against clinical, food and environmental pathogens, such as multidrug-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus and Cryptococcus neoformans. In contrast, the NP2 crude extract displayed antibacterial activity against a limited range of pathogenic and opportunistic pathogens. The serrawettin W1 homologues, in combination with prodigiosin and glucosamine derivatives, produced by pigmented and non-pigmented S. marcescens strains, could thus potentially be employed as broad-spectrum therapeutic agents against multidrug-resistant bacterial and fungal pathogens.


Assuntos
Antibacterianos/farmacologia , Depsipeptídeos/farmacologia , Lipoproteínas/farmacologia , Peptídeos Cíclicos/farmacologia , Prodigiosina/farmacologia , Serratia marcescens/química , Antibacterianos/química , Antibacterianos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Depsipeptídeos/química , Depsipeptídeos/metabolismo , Lipoproteínas/química , Lipoproteínas/metabolismo , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Prodigiosina/química , Prodigiosina/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Metabolismo Secundário , Serratia marcescens/metabolismo , Tensoativos/química , Tensoativos/metabolismo , Tensoativos/farmacologia
3.
Nat Commun ; 10(1): 2992, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278250

RESUMO

Lysocin E, a 37-membered natural depsipeptide, induces rapid bacteriolysis in methicillin-resistant Staphylococcus aureus via a unique menaquinone-dependent mechanism, presenting a promising therapeutic lead. Despite the great medical importance, exploring the potential utility of its derivatives as new platform structures for antibiotic development has remained a significant challenge. Here, we report a high-throughput strategy that enabled the preparation of thousands of analogues of lysocin E and large-scale structure-activity relationship analyses. We integrate 26-step total synthesis of 2401 cyclic peptides, tandem mass spectrometry-sequencing, and two microscale activity assays to identify 23 candidate compounds. Re-synthesis of these candidates shows that 11 of them (A1-A11) exhibit antimicrobial activity superior or comparable to that of lysocin E, and that lysocin E and A1-A11 share L-Leu-6 and L-Ile-11. Therefore, the present strategy allows us to efficiently decipher biologically crucial residues and identify potentially useful agents for the treatment of infectious diseases.


Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Antibacterianos/química , Antibacterianos/uso terapêutico , Química Farmacêutica/métodos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem/métodos
4.
Chem Commun (Camb) ; 55(52): 7434-7437, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31155628

RESUMO

Mortiamides A-D (1-4) are head-to-tail cyclic heptapeptides that were identified from a novel Mortierella sp. isolate obtained from marine sediments from Northern Canada. Herein we report the first total synthesis of mortiamides A-D (1-4) on a solid support by concomitant cyclization/cleavage without any oligomerization side reactions, and overall yields up to 48%. We also report on the antiplasmodial activity of mortiamides A-D (1-4). We show that three out of the four tested mortiamides (A, B and D) have moderate antiplasmodial activity, while mortiamide D (4) exhibits low micromolar activity.


Assuntos
Antimaláricos/síntese química , Peptídeos Cíclicos/síntese química , Antimaláricos/farmacologia , Ciclização , Peptídeos Cíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Polimerização
5.
Nat Chem ; 11(7): 644-652, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182821

RESUMO

A promising approach in cancer therapy is to find ligands that directly bind ubiquitin (Ub) chains. However, finding molecules capable of tightly and specifically binding Ub chains is challenging given the range of Ub polymer lengths and linkages and their subtle structural differences. Here, we use total chemical synthesis of proteins to generate highly homogeneous Ub chains for screening against trillion-member macrocyclic peptide libraries (RaPID system). De novo cyclic peptides were found that can bind tightly and specifically to K48-linked Ub chains, confirmed by NMR studies. These cyclic peptides protected K48-linked Ub chains from deubiquitinating enzymes and prevented proteasomal degradation of Ub-tagged proteins. The cyclic peptides could enter cells, inhibit growth and induce programmed cell death, opening new opportunities for therapeutic intervention. This highly synthetic approach, with both protein target generation and cyclic peptide discovery performed in vitro, will make other elaborate post-translationally modified targets accessible for drug discovery.


Assuntos
Lisina/química , Peptídeos Cíclicos/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Ubiquitinas/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Células HeLa , Humanos , Estrutura Molecular , Peptídeos Cíclicos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Ligação Proteica , Bibliotecas de Moléculas Pequenas/farmacologia , Ubiquitinas/síntese química , Ubiquitinas/química
6.
Nat Commun ; 10(1): 2730, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227691

RESUMO

Recently our groups discovered lugdunin, a new cyclic peptide antibiotic that inhibits Staphylococcus aureus epithelial colonization in humans and rodents. In this work, we analyzed its immuno-modulatory and antimicrobial potential as a single agent or in combination with other microbiota- or host-derived factors. We show that pretreatment of primary human keratinocytes or mouse skin with lugdunin in combination with microbiota-derived factors results in a significant reduction of S. aureus colonization. Moreover, lugdunin increases expression and release of LL-37 and CXCL8/MIP-2 in human keratinocytes and mouse skin, and results in the recruitment of monocytes and neutrophils in vivo, both by a TLR/MyD88-dependent mechanism. Interestingly, S. aureus elimination by lugdunin is additionally achieved by synergistic antimicrobial activity with LL-37 and dermcidin-derived peptides. In summary, our results indicate that lugdunin provides multi-level protection against S. aureus and may thus become a promising treatment option for S. aureus skin infections in the future.


Assuntos
Antibacterianos/farmacologia , Imunidade Inata/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Tiazolidinas/farmacologia , Animais , Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/imunologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microbiota/efeitos dos fármacos , Microbiota/imunologia , Peptídeos/imunologia , Peptídeos Cíclicos/uso terapêutico , Cultura Primária de Células , Pele/efeitos dos fármacos , Pele/imunologia , Pele/microbiologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Tiazolidinas/uso terapêutico
7.
Molecules ; 24(9)2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31083642

RESUMO

Lipogenesis plays a critical role in the growth and metastasis of tumors, which is becoming an attractive target for anti-tumor drugs. RA-XII, one of the cyclopeptide glycosides isolated from Rubia yunnanensis, exerts anti-tumor effects on liver cancer. However, the underlying mechanisms are not clear. In the present study, the effects of RA-XII on lipogenesis were evaluated and the underlying mechanisms were investigated. The results indicated that RA-XII strongly inhibited tumor growth and lipogenesis (triglycerides and lipid droplets) in HepG2 cells, and the expression of key factors involved in lipogenesis (SREBP, SCD, FASN) was also obviously downregulated. Further investigation showed that the anti-tumor effects of RA-XII were attenuated by SREBP knockdown. Moreover, RA-XII downregulated the expression of SREBP cleavage-activating protein (SCAP), an upstream regulator of SREBP, and siRNA of SCAP prevented its restrained effects on tumor growth and lipogenesis. In addition, the in vivo experiment showed that RA-XII strongly restrained the lipogenesis and growth of liver tumor in nude mice xenograft model. Taken together, these results indicate that RA-XII suppresses the liver cancer growth by inhibition of lipogenesis via SCAP-dependent SREBP suppression. The findings reveal the potentials of RA-XII to be used in a novel therapeutic approach for treating liver cancer.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipogênese/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Peptídeos Cíclicos/uso terapêutico , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos Cíclicos/farmacologia
8.
Mar Drugs ; 17(4)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991727

RESUMO

Marine sponges are a prolific source of bioactive compounds. In this work, the putative antiangiogenic potential of a series of synthetic precursors of Solomonamide A, a cyclic peptide isolated from a marine sponge, was evaluated. By means of an in vitro screening, based on the inhibitory activity of endothelial tube formation, the compound Solo F-OH was selected for a deeper characterization of its antiangiogenic potential. Our results indicate that Solo F-OH is able to inhibit some key steps of the angiogenic process, including the proliferation, migration, and invasion of endothelial cells, as well as diminish their capability to degrade the extracellular matrix proteins. The antiangiogenic potential of Solo F-OH was confirmed by means of two different in vivo models: the chorioallantoic membrane (CAM) and the zebrafish yolk membrane (ZFYM) assays. The reduction in ERK1/2 and Akt phosphorylation in endothelial cells treated with Solo F-OH denotes that this compound could target the upstream components that are common to both pathways. Taken together, our results show a new and interesting biological activity of Solo F-OH as an inhibitor of the persistent and deregulated angiogenesis that characterizes cancer and other pathologies.


Assuntos
Inibidores da Angiogênese/farmacologia , Peptídeos Cíclicos/farmacologia , Inibidores da Angiogênese/química , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Membrana Corioalantoide , Células Endoteliais/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Estrutura Molecular , Proteína Oncogênica v-akt/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos Cíclicos/química , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra
9.
Chemistry ; 25(37): 8894-8902, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31012978

RESUMO

Cyclomarins are highly potent antimycobacterial and antiplasmodial cyclopeptides isolated from a marine bacterium (Streptomyces sp.). Previous studies have identified the target proteins and elucidated a novel mode of action, however there are currently only a few studies examining the structure-activity relationship (SAR) for both pathogens. Herein, we report the synthesis and biological evaluation of 17 novel desoxycyclomarin-inspired analogues. Optimization via side chain modifications of the non-canonical amino acids led to potent lead structures for each pathogen.


Assuntos
Antibacterianos/síntese química , Antimaláricos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antibacterianos/farmacologia , Antimaláricos/farmacologia , Concentração Inibidora 50 , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/química , Estereoisomerismo , Relação Estrutura-Atividade
10.
Food Microbiol ; 82: 62-69, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31027820

RESUMO

The aim of this work was to elucidate the role of the secondary metabolites produced by B. amyloliquefaciens BUZ-14 against B. cinerea, M. fructicola, M. laxa, P. digitatum, P. italicum and P. expansum both in vitro and in planta. The entire cell free supernatant (CFS) and the lipopeptide fraction (LPF) showed similar antifungal activities, completely inhibiting all the fungi at dilutions of 1:24 or even lower, whereas the non-butanolic fraction (NBF) barely inhibited the fungi. However, when the LPF and CFS were applied on fruit, only brown rot in peaches and blue rot in apples was totally inhibited. The main families of metabolites in the LPF were iturin A, fengycin and surfactin with maximum concentrations of 407, 853 and 658 µg mL-1, respectively. Subsequently, a TLC-bioautography revealed iturin A as the key metabolite in the inhibitions and allowed us to establish in vivo MICs of 16.9 and 33.9 µg mL-1 for Monilinia species and P. expansum, respectively. The application of 24 h-old BUZ-14 cultures suppressed brown rot in peaches and also blue rot in apples but failed to inhibit the other diseases. However, BUZ-14 was only able to grow and produce iturin A in peaches so we can deduce that the amount of iturin A brought with the cultures (36 ±â€¯14 µg mL-1) could be enough to control both diseases. The strong antifungal activity of the iturin A present in the BUZ-14 CFS suggests that it could be successfully used for postharvest disease control. However, future research is necessary to maximize the iturin A production by B. amyloliquefaciens BUZ-14 in order to optimize a commercial application.


Assuntos
Bacillus amyloliquefaciens/química , Frutas/microbiologia , Fungicidas Industriais/farmacologia , Peptídeos Cíclicos/farmacologia , Prunus persica/microbiologia , Antibiose , Contaminação de Alimentos/prevenção & controle , Testes de Sensibilidade Microbiana , Metabolismo Secundário
11.
Molecules ; 24(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978971

RESUMO

Cell-penetrating peptide [WR]5 has been previously shown to be an efficient molecular transporter for various hydrophilic and hydrophobic molecules. The peptide was synthesized using Fmoc/tBu solid-phase chemistry, and one arginine was replaced with one lysine to enable the conjugation with the anticancer drugs. Paclitaxel (PTX) was functionalized with an esterification reaction at the C2' hydroxyl group of PTX with glutaric anhydride and conjugated with the cyclic peptide [W(WR)4K(ßAla)] in DMF to obtain the peptide-drug conjugate PTX1. Furthermore, camptothecin (CPT) was modified at the C(20)-hydroxyl group through the reaction with triphosgene. Then, it was conjugated with two functionalized cyclic peptides through a formyl linker affording two different conjugates, namely CPT1 and CPT2. All the conjugates showed better water solubility as compared to the parent drug. The cytotoxicity assay of the drugs and their conjugates with the peptides were evaluated in the human breast cancer MCF-7 cell line. PTX inhibited cell proliferation by 39% while the PTX-peptide conjugate inhibited the proliferation by ~18% after 72 h incubation. On the other hand, CPT, CPT1, and CPT2 reduced the cell proliferation by 68%, 39%, and 62%, respectively, in the MCF-7 cell lines at 5 µM concentration after 72 h incubation.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Peptídeos Penetradores de Células/farmacologia , Peptídeos Cíclicos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Neoplasias da Mama/patologia , Camptotecina/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/síntese química , Peptídeos Penetradores de Células/química , Esterificação , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Paclitaxel/química , Paclitaxel/farmacologia , Peptídeos Cíclicos/síntese química , Técnicas de Síntese em Fase Sólida
12.
Appl Microbiol Biotechnol ; 103(11): 4377-4392, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30997554

RESUMO

Candida albicans is a fungal pathogen that is difficult to cure clinically. The current clinic C. albicans-inhibiting drugs are very harmful to humans. This study revealed the potential of iturin fractions from Bacillus subtilis to inhibit C. albicans in free status (MIC = 32 µg/mL) and natural biofilm in vitro. The inhibition mechanism was identified as an apoptosis pathway via the decrease of mitochondrial membrane potential, the increase of the reactive oxygen species (ROS) accumulation, and the induction of nuclear condensation. For in vivo experiments, the C. albicans infection model was constructed via intraperitoneal injection of 1 × 108C. albicans cells into mice. One day after the infection, iturin was used to treat infected mice at different concentrations alone and in combination with amphotericin B (AmB) by intraperitoneal injection. The treatment with AmB alone could cause the death of infected mice, whereas treatment with 15 mg/kg iturin per day alone led to the survival of all infected mice throughout the study. After continuously treated for 6 days, all mice were sacrificed and analyzed. As results, the combination of 15 mg/kg iturin and AmB at a ratio of 2:1 had the most efficient effect to remove the fungal burden in the kidney and cure the infected mice by reversing the symptoms caused by C. albicans infection, such as the loss of body weight, change of immunology cells in blood and cytokines in serum, and damage of organ structure and functions. Overall, iturin had potential in the development of efficient and safe drugs to cure C. albicans infection.


Assuntos
Antifúngicos/farmacologia , Bacillus subtilis/metabolismo , Candida albicans/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Animais , Antifúngicos/isolamento & purificação , Antifúngicos/uso terapêutico , Biofilmes/efeitos dos fármacos , Candidíase/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/uso terapêutico , Resultado do Tratamento
13.
Biotechnol Lett ; 41(6-7): 651-673, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31020454

RESUMO

The 2,5-diketopiperazines (DKPs) are the smallest cyclopeptides and their basic structure includes a six-membered piperazine nucleus. Typical peptides lack a special functional group in the oligopeptide nucleus. Both are produced by at least 35 representative genera of fungi, and possess huge potential as pharmaceutical drugs and biocontrol agents. To date, only cyclosporin A has been developed into a commercial product. This review summarises 186 fungi-derived compounds reported since 2000. Antibiotic (antibacterial, antifungal, synergistic antifungal, antiviral, antimycobacterial, antimalarial, antileishmanial, insecticidal, antitrypanosomal, nematicidal and antimicroalgal) activities are discussed for 107 of them, including 66 DKPs (14 epipolythiodioxopiperazines, 20 polysulphide bridge-free thiodiketopiperazines, and 32 sulphur-free prenylated indole DKPs), 15 highly N-methylated, and 26 non-highly N-methylated typical peptides. Structure-activity relationships, mechanisms of action, and research methods are covered in detail. Additionally, biosynthases of tardioxopiperazines and neoechinulins are highlighted. These compounds have attracted considerable interest within the pharmaceutical and agrochemical industries.


Assuntos
Anti-Infecciosos/farmacologia , Descoberta de Drogas/tendências , Fungos/metabolismo , Peptídeos Cíclicos/farmacologia , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/metabolismo , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/metabolismo
14.
Chem Commun (Camb) ; 55(38): 5471-5474, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31012472

RESUMO

Stylissatin A, an anti-inflammatory cyclic heptapeptide, and its derivatives potently inhibited the differentiation of preadipocytes and reduced triglyceride accumulation in mature adipocytes, with little cytotoxicity. Our studies might contribute to the development of leads for new anti-inflammatory and anti-obesity agents.


Assuntos
Adipócitos/efeitos dos fármacos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Poríferos/química , Células 3T3-L1 , Adipócitos/citologia , Animais , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Células RAW 264.7 , Água do Mar , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 174: 56-65, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029944

RESUMO

A zinc(II) phthalocyanine substituted with three 2,4-dinitrobenzenesulfonate (DNBS) groups and a cyclic arginine-glycine-aspartic acid (cRGDfK) moiety was prepared and characterized. With three strongly electron-withdrawing DNBS groups, this compound was fully quenched in terms of fluorescence emission and singlet oxygen generation in N,N-dimethylformamide and phosphate buffered saline due to the strong photoinduced electron transfer effect. In the presence of glutathione (GSH), which is the most abundant intracellular thiol particularly in tumor cells, the DNBS moieties were cleaved, thereby restoring these photoactivities and making the conjugate as a GSH-activated photosensitizer. Being a well-known integrin antagonist, the cyclic RGD peptide sequence could enhance the localization of the conjugate in integrin-upregulated tumor cells. As shown by confocal laser scanning microscopy and flow cytometry, the intracellular fluorescence intensity of the conjugate was significantly higher in the integrin-positive A549 and MDA-MB-231 cells than in the integrin-negative MCF-7 and HEK293 cells. The photocytotoxicity of the conjugate against MDA-MB-231 cells was also higher than that toward MCF-7 cells. The results suggest that this dual-functional photosensitizer is a promising candidate for targeted photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Glutationa/metabolismo , Indóis/farmacologia , Peptídeos Cíclicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/efeitos da radiação , Benzenossulfonatos/síntese química , Benzenossulfonatos/metabolismo , Benzenossulfonatos/farmacologia , Benzenossulfonatos/efeitos da radiação , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/efeitos da radiação , Fluorescência , Células HEK293 , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/efeitos da radiação , Integrinas/metabolismo , Luz , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/efeitos da radiação , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo , Zinco/química
16.
Appl Microbiol Biotechnol ; 103(10): 3931-3940, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30915503

RESUMO

Lasso peptides are ribosomally synthesized and post-translationally modified natural products with a characteristic slipknot-like structure, which confers these peptides remarkable stability and diverse pharmacologically relevant bioactivities. Among all the reported lasso peptides, lassomycin and lariatins are unique lasso peptides that exhibit noticeable anti-tuberculosis (TB) activity. Due to the unique threaded structure and the unusual bactericidal mechanism toward Mycobacterium tuberculosis, these peptides have drawn considerable interest, not only in the field of total synthesis but also in several other fields including biosynthesis, bioengineering, and structure-activity studies. During the past few years, significant progress has been made in understanding the biosynthetic mechanism of these intriguing compounds, which has provided a solid foundation for future work. This review highlights recent achievements in the discovery, structure elucidation, biological activity, and the unique anti-TB mechanism of lasso peptides. Moreover, the discovery of their biosynthetic pathway has laid the foundation for combinatorial biosynthesis of their analogs, which provides new perspectives for the production of novel anti-TB lasso peptides.


Assuntos
Antituberculosos/farmacologia , Descoberta de Drogas/tendências , Mycobacterium tuberculosis/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Tecnologia Farmacêutica/métodos , Antituberculosos/isolamento & purificação , Antituberculosos/metabolismo , Biotecnologia/métodos , Peptídeos Cíclicos/biossíntese , Peptídeos Cíclicos/isolamento & purificação , Tuberculose/tratamento farmacológico
17.
Nat Commun ; 10(1): 1149, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850614

RESUMO

Treatment failure in biofilm-associated bacterial infections is an important healthcare issue. In vitro studies and mouse models suggest that bacteria enter a slow-growing/non-growing state that results in transient tolerance to antibiotics in the absence of a specific resistance mechanism. However, little clinical confirmation of antibiotic tolerant bacteria in patients exists. In this study we investigate a Staphylococcus epidermidis pacemaker-associated endocarditis, in a patient who developed a break-through bacteremia despite taking antibiotics to which the S. epidermidis isolate is fully susceptible in vitro. Characterization of the clinical S. epidermidis isolates reveals in-host evolution over the 16-week infection period, resulting in increased antibiotic tolerance of the entire population due to a prolonged lag time until growth resumption and a reduced growth rate. Furthermore, we observe adaptation towards an increased biofilm formation capacity and genetic diversification of the S. epidermidis isolates within the patient.


Assuntos
Antibacterianos/farmacologia , Bacteriemia/microbiologia , Resistência a Múltiplos Medicamentos/genética , Endocardite/microbiologia , Interações Hospedeiro-Patógeno/genética , Infecções Estafilocócicas/microbiologia , Staphylococcus epidermidis/genética , Adulto , Bacteriemia/tratamento farmacológico , Bacteriemia/patologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Tolerância a Medicamentos/genética , Endocardite/tratamento farmacológico , Endocardite/patologia , Evolução Molecular , Fluoroquinolonas/farmacologia , Glicopeptídeos/farmacologia , Humanos , Mutação INDEL , Masculino , Testes de Sensibilidade Microbiana , Marca-Passo Artificial/microbiologia , Peptídeos Cíclicos/farmacologia , Filogenia , Polimorfismo de Nucleotídeo Único , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/patologia , Staphylococcus epidermidis/efeitos dos fármacos , Staphylococcus epidermidis/crescimento & desenvolvimento , Staphylococcus epidermidis/isolamento & purificação , beta-Lactamas/farmacologia
18.
Eur J Med Chem ; 169: 65-75, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30856407

RESUMO

Physiological and pathological angiogenesis is mainly regulated by the binding of the vascular endothelial growth factor (VEGF) to its receptors (VEGFRs). Antagonists of VEGFR are very attractive for the treatment of diseases related to excessive angiogenesis. Our previously designed C-terminal alkylated cyclic peptides [YKDEGLEE]-NHR (R = alkyl, arylalkyl) disrupt the interaction between VEGF and VEGFRs in biological assays. In this paper, we described the structural studies of the binding of one of these cyclic peptides named Peptide 3 to the VEGFR1 domain 2 (VEGFR1-D2). The molecular docking and NMR mapping identified the binding site on VEGFR1-D2. The anti-angiogenic effect of our peptide was evaluated by an experiment of VEGF-induced tube formation in two cell lines, retinal cell type RF6/A and vascular endothelial cell type HUVEC. Some new peptides were also synthesized and compared by an ELISA-based assay, in order to verify their ability to disrupt the formation of the complex VEGF-A/VEGFR1. In conclusion, the structural studies of Peptide 3 with VEGFR1-D2 will help the design of more efficient VEGFR antagonists. Moreover, Peptide 3, with improved receptor binding affinity, could be more suitable for VEGFR targeting bioimaging studies once labeled.


Assuntos
Inibidores da Angiogênese/farmacologia , Peptídeos Cíclicos/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/química , Animais , Sítios de Ligação/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Estrutura Molecular , Peptídeos Cíclicos/química , Relação Estrutura-Atividade , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
Chem Commun (Camb) ; 55(29): 4198-4201, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30896003

RESUMO

Peptides that induced autophagy at micromolar concentrations with improved proteolytic resistance properties were generated using the facile methionine bis-alkylation method. Notably, a short bicyclic peptide 7f was proven to be the most potent one among the designed peptides in regards to autophagy inducing activity. This study facilitated the development of a peptide-based autophagy inducer and demonstrated the potential applications of the methionine alkylation-based macrocyclization method for the diversity-oriented generation of peptide-based autophagy inducers.


Assuntos
Autofagia/efeitos dos fármacos , Metionina/química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Alquilação , Sequência de Aminoácidos , Células HeLa , Humanos
20.
J Enzyme Inhib Med Chem ; 34(1): 728-739, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30822267

RESUMO

The most challenging issue facing peptide drug development is producing a molecule with optimal physical properties while maintaining target binding affinity. Masking peptides with protecting groups that can be removed inside the cell, produces a cell-permeable peptide, which theoretically can maintain its biological activity. Described are series of prodrugs masked using: (a) O-alkyl, (b) N-alkyl, and (c) acetyl groups, and their binding affinity for Hsp90. Alkyl moieties increased compound permeability, Papp, from 3.3 to 5.6, however alkyls could not be removed by liver microsomes or in-vivo and their presence decreased target binding affinity (IC50 of ≥10 µM). Thus, unlike small molecules, peptide masking groups cannot be predictably removed; their removal is related to the 3-D conformation. O-acetyl groups were cleaved but are labile, increasing challenges during synthesis. Utilising acetyl groups coupled with mono-methylated amines may decrease the polarity of a peptide, while maintaining binding affinity.


Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Peptídeos Cíclicos/farmacologia , Pró-Fármacos/farmacologia , Animais , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Relação Estrutura-Atividade
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