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1.
Antibiotics (Basel) ; 10(10)2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34680817

RESUMO

The emergence and spread of multiple drug-resistant bacteria strains caused the development of new antibiotics to be one of the most important challenges of medicinal chemistry. Despite many efforts, the commercial availability of peptide-based antimicrobials is still limited. The presented study aims to explain that immobilized artificial membrane chromatography can support the characterization of antimicrobial peptides. Consequently, the chromatographic experiments of three groups of related peptide substances: (i) short cationic lipopeptides, (ii) citropin analogs, and (iii) conjugates of ciprofloxacin and levofloxacin, with a cell-penetrating peptide were discussed. In light of the discussion of the mechanisms of action of these compounds, the obtained results were interpreted.

2.
Molecules ; 26(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445797

RESUMO

A major obstacle in tumor treatment is associated with the poor penetration of a therapeutic agent into the tumor tissue and with their adverse influence on healthy cells, which limits the dose of drug that can be safely administered to cancer patients. Gemcitabine is an anticancer drug used to treat a wide range of solid tumors and is a first-line treatment for pancreatic cancer. The effect of gemcitabine is significantly weakened by its rapid plasma degradation. In addition, the systemic toxicity and drug resistance significantly reduce its chemotherapeutic efficacy. Up to now, many approaches have been made to improve the therapeutic index of gemcitabine. One of the recently developed approaches to improve conventional chemotherapy is based on the direct targeting of chemotherapeutics to cancer cells using the drug-peptide conjugates. In this work, we summarize recently published gemcitabine peptide-based conjugates and their efficacy in anticancer therapy.


Assuntos
Desoxicitidina/análogos & derivados , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Peptídeos/uso terapêutico , Animais , Peptídeos Penetradores de Células/farmacologia , Peptídeos Penetradores de Células/uso terapêutico , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Humanos , Nanopartículas/química , Peptídeos/farmacologia
3.
Metallomics ; 12(12): 2199, 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33320153

RESUMO

Correction for 'Stability of Cu(ii) complexes with FomA protein fragments containing two His residues in the peptide chain' by Monika Katarzyna Lesiów et al., Metallomics, 2019, 11, 1518-1531, DOI: 10.1039/C9MT00131J.

4.
J Inorg Biochem ; 212: 111250, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32920436

RESUMO

Mono- and dinuclear Cu(II) complexes with Ac-PTVHNEYH-NH2 (L1) and Ac-NHHTLND-NH2 (L2) peptides from FomA protein of Fusobacterium nucleatum were studied by potentiometry, spectroscopic methods (UV-Vis, CD, EPR) and MS technique. The dominant mononuclear complexes for L1 ligand are: CuHL (pH range 5.0-6.0) with 2N {2Nim}, CuH-2L (pH range 8.0-8.5) and CuH-3L species (above pH 9.0) with 4N {Nim, 3N-} coordination modes. The complexes: CuH-1L with 3N {2Nim, N-}, CuH-2L with 3N {Nim, 2N-} and CuH-3L with 4N {Nim, 3N-} binding sites are proposed for the L2 ligand. Probably in the CuH-2L complex for CuL2 system the second His residue in His-His sequence is bound to Cu(II) ion, while the first His residue may stabilize this complex by His-His and/or His-Cu(II) interactions. The dominant dinuclear Cu2L1 complexes in the pH range 6.5-10.5 are: the Cu2H-4L and Cu2H-6L species with 3N{Nim, 2N-}4N{Nim, 3N-} and 4N{Nim, 3N-}4N{Nim, 3N-} binding sites, respectively. In the case of the Cu2L2 complex in the pH range 7.2-10.5, the Cu2H-4L and Cu2H-7L species dominate with 2N{Nim, N-}4N{Nim, 3N-} and (Cu(OH)42-4N{Nim, 3N-}) coordination modes, respectively. The ability to generate reactive oxygen species (ROS) by uncomplexed Cu(II) ions, ligands and their complexes at pH 7.4 in the presence of hydrogen peroxide or ascorbic acid was studied. UV-Vis, luminescence, EPR spin trapping and gel electrophoresis methods were used. Both complexes produce higher level of ROS compared to those of their ligands. ROS produced by Cu(II) complexes are hydroxyl radical and singlet oxygen, which contribute to oxidative DNA cleavage.


Assuntos
Proteínas da Membrana Bacteriana Externa/metabolismo , Complexos de Coordenação/metabolismo , Cobre/metabolismo , DNA/metabolismo , Histidina/metabolismo , Peptídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Motivos de Aminoácidos , Fusobacterium nucleatum/metabolismo , Histidina/química , Potenciometria , Análise Espectral/métodos
5.
Int J Mol Sci ; 21(13)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32630159

RESUMO

Seven conjugates composed of well-known fluoroquinolone antibacterial agents, ciprofloxacin (CIP) or levofloxacin (LVX), and a cell-penetrating peptide transportan 10 (TP10-NH2) were synthesised. The drugs were covalently bound to the peptide via an amide bond, methylenecarbonyl moiety, or a disulfide bridge. Conjugation of fluoroquinolones to TP10-NH2 resulted in congeners demonstrating antifungal in vitro activity against human pathogenic yeasts of the Candida genus (MICs in the 6.25 - 100 µM range), whereas the components were poorly active. The antibacterial in vitro activity of most of the conjugates was lower than the activity of CIP or LVX, but the antibacterial effect of CIP-S-S-TP10-NH2 was similar to the mother fluoroquinolone. Additionally, for two representative CIP and LVX conjugates, a rapid bactericidal effect was shown. Compared to fluoroquinolones, TP10-NH2 and the majority of its conjugates generated a relatively low level of reactive oxygen species (ROS) in human embryonic kidney cells (HEK293) and human myeloid leukemia cells (HL-60). The conjugates exhibited cytotoxicity against three cell lines, HEK293, HepG2 (human liver cancer cell line), and LLC-PK1 (old male pig kidney cells), with IC50 values in the 10 - 100 µM range and hemolytic activity. The mammalian toxicity was due to the intrinsic cytoplasmic membrane disruption activity of TP10-NH2 since fluoroquinolones themselves were not cytotoxic. Nevertheless, the selectivity index values of the conjugates, both for the bacteria and human pathogenic yeasts, remained favourable.


Assuntos
Anti-Infecciosos/síntese química , Antineoplásicos/síntese química , Peptídeos Penetradores de Células , Ciprofloxacina , Levofloxacino , Proteínas Recombinantes de Fusão , Animais , Anti-Infecciosos/farmacologia , Candida/efeitos dos fármacos , Candida/metabolismo , Farmacorresistência Bacteriana , Células HEK293 , Células HL-60 , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Suínos
6.
Biochimie ; 171-172: 178-186, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32169666

RESUMO

A gradual truncation of the primary structure of frog skin-derived Huia versabilis Bowman-Birk peptidic inhibitor (HV-BBI) resulted in 18-times stronger inhibitor of matriptase-1 (peptide 6, Ki = 8 nm) in comparison to the full-length HV-BBI (Ki = 155 nm). Analogous increase in the inhibitory activity in correlation with the peptide length reduction was not observed in case of other serine proteases, bovine trypsin (Ki = 151 nm for peptide 6 and Ki = 120 nm for HV-BBI) and plasmin (Ki = 120 nm for peptide 6 and 82 nm for HV-BBI). Weaker binding affinity to these enzymes emphasized an inhibitory specificity of peptide 6. Molecular dynamic analysis revealed that the observed variations in the binding affinity of peptide 6 and HV-BBI with matriptase-1 are associated with the entropic differences of the unbound peptides. Moreover, several aspects explaining differences in the inhibition of matriptase-1 by peptide 6 (bearing the C-terminal amide group) and its two analogues, peptide 6∗ (having the C-terminal carboxyl group, Ki = 473 nm) and cyclic peptide 6∗∗ (Ki = 533 nm), both exhibiting more than 50-fold reduced inhibitory potency, were discovered. It was also shown that peptide 6 presented significantly higher resistance to proteolytic degradation in human serum than HV-BBI. Additional investigations revealed that, in contrast to some amphibian-derived inhibitors, HV-BBI and its truncated analogues do not possess bactericidal activity, thus they cannot be considered as bifunctional agents.


Assuntos
Peptídeos , Serina Endopeptidases/metabolismo , Animais , Bovinos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Peptídeos/química , Peptídeos/farmacologia , Proteólise
7.
ACS Chem Biol ; 14(10): 2233-2242, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31513374

RESUMO

Recent studies have shown that modified human lactoferrin 20-31 fragment, named HLopt2, possesses antibacterial and antifungal activity. Thus, we decided to synthesize and evaluate the biological activity of a series of conjugates based on this peptide and one of the antimicrobials with proven antibacterial (ciprofloxacin, CIP, and levofloxacin, LVX) or antifungal (fluconazole, FLC) activity. The drugs were covalently connected to the peptide via amide, methylenecarbonyl moieties, or a disulfide bridge. The antibacterial and antifungal activities were evaluated under Clinical and Laboratory Standard Institute (CLSI) recommended conditions or in a low-salt brain-heart infusion diluted medium (BHI1/100). Results showed that conjugation of the peptide with the drug increased its antimicrobial activity up to 4-fold. Under CLSI-recommended conditions, all the compounds revealed rather low efficiency. Among conjugates, the highest antibacterial activity was recorded for the CIP-Cys-S-S-HLopt2-NH2 (III). In BHI1/100, which had lower differentiating properties, all of the conjugates revealed low MIC and MMC (minimum inhibitory and microbicidal concentrations) values. The disulfide bridge used as a linker in the most active conjugate (III) upon incubation with S. aureus cells is reduced, releasing constituent peptide and CIP-Cys. In addition, we showed that its fluorescently labeled analogue and constituent peptide are able to be internalized into both C. albicans and S. aureus cells. Moreover, the invaluable advantage of the presented conjugates was their low toxicity to mammalian cells and very low hemolytic activity. The current research can form a solid basis for further in vivo studies and drug development.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Imunoconjugados/farmacologia , Lactoferrina/farmacologia , Fragmentos de Peptídeos/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/toxicidade , Antifúngicos/síntese química , Antifúngicos/toxicidade , Candida albicans/efeitos dos fármacos , Ciprofloxacina/síntese química , Ciprofloxacina/farmacologia , Ciprofloxacina/toxicidade , Estabilidade de Medicamentos , Escherichia coli/efeitos dos fármacos , Fluconazol/síntese química , Fluconazol/farmacologia , Fluconazol/toxicidade , Células HEK293 , Células Hep G2 , Humanos , Imunoconjugados/toxicidade , Lactoferrina/síntese química , Lactoferrina/toxicidade , Levofloxacino/síntese química , Levofloxacino/farmacologia , Levofloxacino/toxicidade , Masculino , Testes de Sensibilidade Microbiana , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/toxicidade , Staphylococcus aureus/efeitos dos fármacos , Suínos
8.
Peptides ; 117: 170079, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959143

RESUMO

Eight new peptide conjugates composed of modified bovine lactoferricin truncated analogues (LFcinB) and one of the three antimicrobials - ciprofloxacin (CIP), levofloxacin (LVX), and fluconazole (FLC) - were synthesized. Four different linkers were applied to connect a peptide and an antimicrobial agent. The FLC-containing peptidic conjugates were synthesized using the "click chemistry" method. This novel approach is reported here for the first time. Unlike their components, CIP- and LVX-based conjugates exerted activity against Candida yeast. Similarly to the constituent peptides, synthesized conjugates showed activity against Gram-positive bacteria, especially S. epidermidis. The most active were the conjugates containing CIP linked to the peptide by the redox-sensitive disulfide bridge. Our results show a significant role of a linker between antimicrobial agent and a peptide. This was also confirmed by the lack of synergistic effects on the antimicrobial activity of the constituent compounds. Moreover, cytotoxicity assays revealed that the proposed conjugates cause a comparatively low cytotoxic effect in reference to antibiotics widely used in therapies. Therefore, they can be deliberated as attractive leading structures for the development of drugs.


Assuntos
Anti-Infecciosos , Candida/crescimento & desenvolvimento , Lactoferrina , Peptídeos , Staphylococcus epidermidis/crescimento & desenvolvimento , Células A549 , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Células HL-60 , Humanos , Lactoferrina/química , Lactoferrina/farmacologia , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia
9.
Future Med Chem ; 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30518272

RESUMO

Matriptase-2 (MT2) is a membrane-anchored proteolytic enzyme. It acts as the proteolytic key regulator in human iron homeostasis. A high expression level can lead to iron overload diseases, whereas mutations in the gene encoding MT2, TMPRSS6, may result in various forms of iron deficiency anemia. Recently, MT2 has been reported as a positive prognostic factor in breast and prostate cancers. However, the exact functions of MT2 in various pathophysiological conditions are still not fully understood. In this review, we describe the synthetic tools designed and synthesized to regulate or monitor MT2 proteolytic activity and present the latest knowledge about the role of MT2 in iron homeostasis and cancer.

10.
J Inorg Biochem ; 189: 69-80, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30243120

RESUMO

Fusobacterium nucleatum is an anaerobic, Gram-negative bacteria linked to colon cancer. It is interesting to determine how metal ions interact with bacterial adhesin proteins. To this end, the coordination of ATDAAS-NH2 and MKKFL-NH2 fragments of Fusobacterium adhesin A (FadA) to copper(II) ions was studied by potentiometry, spectroscopic techniques (UV-Vis, CD, EPR and NMR) and the density functional theory (DFT) methods. At pH 6.8 (colon physiological pH), the metal ion in the first peptide (ATDAAS-NH2) is coordinated by one oxygen and three nitrogen donors while in the second one (MKKFL-NH2) - by sulfur and three nitrogen atoms. Both complexes form two five- and one six-membered stable chelate rings. Moreover, reactivity studies confirmed the production of reactive oxygen species such as hydroxyl radical, superoxide anion radical and singlet oxygen. Generation of reactive oxygen species (ROS) was observed during gel electrophoresis and spectroscopic assays with reporting molecules like NDMA (N,N-dimethyl-p-nitrosoaniline) and NBT (Nitrotetrazolium Blue Chloride). All reactions were conducted in the presence of hydrogen peroxide as endogenous oxidant.


Assuntos
Adesinas Bacterianas/química , Cobre/química , Fusobacterium nucleatum/química , Espectroscopia de Ressonância de Spin Eletrônica , Concentração de Íons de Hidrogênio , Potenciometria , Espécies Reativas de Oxigênio/química , Superóxidos/química
11.
Bioconjug Chem ; 29(9): 3060-3071, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30048118

RESUMO

Three chimera peptides composed of bovine lactoferrampin and the analogue of truncated human neutrophil peptide 1 were synthesized by the solid-phase method. In two compounds peptide chains were connected via isopeptide bond, whereas in the third one disulfide bridge served as a linker. All three chimeras displayed significantly higher antimicrobial activity than the constituent peptides as well as their equimolar mixtures. The one with a disulfide bridge displayed selectivity toward Gram-positive bacteria and was able to penetrate bacterial cells. The chimeric peptides demonstrated low in vitro mammalian cytotoxicity, especially against benign cells. The significance of linker type was also reflected in the secondary structure and proteolytic stability of studied compounds. Presented results proved that such chimeras are good lead structures for designing antimicrobial drugs.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Lactoferrina/química , Fragmentos de Peptídeos/química , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia , alfa-Defensinas/química , Animais , Candida/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Dicroísmo Circular , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/química , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Secundária de Proteína , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
12.
Biopolymers ; 108(2)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27627696

RESUMO

A series of analogues of trypsin inhibitor SFTI-1 were designed and synthesized to monitor peptide splicing. In the middle part of the SFTI-1 analogues, which is released upon incubation with proteinase, the RGD sequence or an acceptor of fluorescence for FRET was introduced. The results of studies with trypsin confirmed that the designed analogues underwent peptide splicing. Furthermore, we showed that a FRET displaying SFTI-1 analogue was internalized into the HaCaT keratinocytes, where it was degraded. Therefore, both proteolysis and the reduction of the disulfide bridge of the peptide took place. As a result, such analogues are a convenient tool to trace the proteolytic activity inside the cell. However, the cytotoxicity of SFTI-1 analogues grafted with the RGD sequence did not correlate with their susceptibility to peptide splicing. Nevertheless, these peptides were slightly more active than the reference peptide (GRGDNP). Interestingly, one of the analogues assigned as [desSer6 ]VI, under experimental conditions, appeared significantly more cytotoxic towards cancer cells U87-MG in contrast to the reference peptide.


Assuntos
Queratinócitos/metabolismo , Peptídeos/metabolismo , Inibidores da Tripsina/metabolismo , Tripsina/metabolismo , Sequência de Aminoácidos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transferência Ressonante de Energia de Fluorescência , Humanos , Queratinócitos/citologia , Espectrometria de Massas , Microscopia de Fluorescência , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Proteólise , Tripsina/química , Inibidores da Tripsina/química
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