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1.
Chem Commun (Camb) ; 56(19): 2917-2920, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32037436

RESUMO

Combinatorial cyclization of hundreds to thousands of random linear peptides by structurally diverse chemical linkers offers access to large macrocyclic compound libraries. A bottleneck in the development of such libraries is the preparation of large numbers of short random linear peptides. Herein, we present a tag-based strategy that is not dependent on a throughput-limiting chromatographic purification step and thus enables parallel production of short peptides. In brief, peptides are synthesized on solid phase as conjugates with a disulfide-linked Cys-Gly-Arg-Trp tetra-peptide tag. The charged arginine residue in the tag allows for purification of the peptides by diethyl ether-precipitation and the tryptophan allows for quantification of the product by absorption measurement. Addition of a reducing agent releases the short peptides from the tag. The released sulfhydryl group in the peptide can readily be used for cyclization of the peptide library with bis-electrophilic linker reagents.


Assuntos
Dissulfetos/química , Oligopeptídeos/química , Cromatografia Líquida , Indicadores e Reagentes/química , Espectrometria de Massas , Oligopeptídeos/síntese química , Oligopeptídeos/isolamento & purificação , Biblioteca de Peptídeos
2.
Chem Commun (Camb) ; 56(4): 615-618, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31833497

RESUMO

Three model arginine-rich tripeptides RXR (X = W, F or non-natural residue 2-napthylalanine) were investigated as antimicrobial agents, with a specific focus to target Pseudomonas aeruginosa through membrane lysis. Activity against biofilms was related to binding of the second messenger molecule, nucleotide bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP). Strong selective activity against P. aeruginosa in planktonic form was observed for RFR and RWR.


Assuntos
Antibacterianos/farmacologia , Arginina/farmacologia , Oligopeptídeos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Arginina/química , Biofilmes/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Modelos Moleculares , Oligopeptídeos/síntese química , Oligopeptídeos/química
3.
Biosci Biotechnol Biochem ; 84(1): 85-94, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794329

RESUMO

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates collagen-mediated platelet activation through its cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs). However, the function of CEACAM1's extracellular cleavage fragments is currently unknown. In the present study, we used mass spectrometry (MS) to identify 9 cleavage fragments shed by matrix metallopeptidase 12 (MMP-12), and then we synthesized peptides with sequences corresponding to the fragments. QLSNGNRTLT (QLSN), a peptide from the A1-domain of CEACAM1, significantly attenuated collagen-induced platelet aggregation. QLSN also attenuated platelet static adhesion to collagen. Additionally, QLSN reduced human platelet secretion and integrin αIIbß3 activation in response to glycoprotein VI (GPVI)-selective agonist, convulxin. Correspondingly, QLSN treatment significantly decreased convulxin-mediated phosphorylation of Src, protein kinase B (Akt), spleen tyrosine kinase (Syk) and phospholipase Cγ2 (PLCγ2) in human platelets. These data indicate that the CEACAM1-derived peptide QLSN inhibits GPVI-mediated human platelet activation. QLSN could potentially be developed as a novel antiplatelet agent.


Assuntos
Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Colágeno/metabolismo , Oligopeptídeos/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/metabolismo , Plaquetas/metabolismo , Proteína Tirosina Quinase CSK/metabolismo , Adesão Celular/efeitos dos fármacos , Venenos de Crotalídeos/farmacologia , Humanos , Motivo de Inibição do Imunorreceptor Baseado em Tirosina/fisiologia , Lectinas Tipo C , Metaloproteinase 12 da Matriz/metabolismo , Oligopeptídeos/síntese química , Fosfolipase C gama/metabolismo , Fosforilação/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/agonistas , Domínios Proteicos/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinase Syk/metabolismo
4.
Int J Nanomedicine ; 14: 7263-7279, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686807

RESUMO

Background: Gemcitabine has been widely used as a chemotherapeutic drug. However, drug resistance, short half-life and side effects seriously decrease its chemotherapeutic efficacy. Purpose: The object of preparing RGDV-gemcitabine was to prolong the half-life, to overcome drug resistance and to eliminate bone marrow toxicity of gemcitabine. Methods: Arg-Gly-Asp-Val was coupled with gemcitabine, forming 4-(Arg-Gly-Asp-Val-amino)-1-[3,3-difluoro-4-hydroxy-5-(hydroxylmethyl)oxo-lan-2-yl]pyrimidin-2-one (RGDV-gemcitabine) involving 9-step reactions. The advantages of RGDV-gemcitabine to gemcitabine were demonstrated by a series of assays, such as in vitro half-life assay, in vitro drug resistance assay, in vivo anti-tumor assay, in vivo kidney toxicity assay, in vivo liver toxicity assay and in vivo marrow toxicity assay. The nano-features of RGDV-gemcitabine were visualized by TEM, SEM and AFM images. The tumor-targeting action and release of RGDV-gemcitabine were evidenced by FT-MS spectra. Results: Half-life and anti-tumor activity of RGDV-gemcitabine were 17-fold longer and 10-fold higher than that of gemcitabine, respectively. RGDV-gemcitabine, but not gemcitabine, showed no kidney toxicity, no liver toxicity, no marrow toxicity and no drug resistance. The advantages attributed to the nanofeatures of RGDV-gemcitabine were targeting tumor tissue and releasing gemcitabine in tumor tissue. Conclusion: RGDV-gemcitabine successively overcame the defects of gemcitabine and provided a practical strategy of nano-medicine.


Assuntos
Medula Óssea/patologia , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Nanomedicina , Oligopeptídeos/farmacologia , Alanina Transaminase/sangue , Animais , Antineoplásicos/farmacologia , Aspartato Aminotransferases/sangue , Linhagem Celular Tumoral , Desoxicitidina/efeitos adversos , Desoxicitidina/síntese química , Desoxicitidina/química , Meia-Vida , Humanos , Concentração Inibidora 50 , Masculino , Camundongos Endogâmicos ICR , Oligopeptídeos/síntese química , Oligopeptídeos/química , Tamanho da Partícula , Eletricidade Estática
5.
Chem Commun (Camb) ; 55(91): 13653-13656, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31593201

RESUMO

Blending synthetic biology and synthetic chemistry represents a powerful approach to diversity complex molecules. To further enable this, compatible synthetic tools are needed. We report the first Buchwald Hartwig amination reactions with unprotected halotryptophans under aqueous conditions and demonstrate this methodology is applicable also to the modification of unprotected tripeptides and the natural product barettin.


Assuntos
Oligopeptídeos/química , Peptídeos Cíclicos/química , Triptofano/análogos & derivados , Água/química , Aminação , Compostos de Anilina/química , Catálise , Halogênios/química , Oligopeptídeos/síntese química , Paládio/química , Triptofano/síntese química
6.
Chemistry ; 25(69): 15759-15764, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31628819

RESUMO

A general and robust method for the incorporation of aspartates with a thioacid side chain into peptides has been developed. Pseudoproline tripeptides served as building blocks for the efficient fluorenylmethyloxycarbonyl (Fmoc) solid-phase synthesis of thioacid-containing peptides. These peptides were readily converted to complex N-glycopeptides by using a fast and chemoselective one-pot deprotection/ligation procedure. Furthermore, a novel side reaction that can lead to site-selective peptide cleavage using thioacids (CUT) was discovered and studied in detail.


Assuntos
Glicopeptídeos/síntese química , Oligopeptídeos/química , Prolina/análogos & derivados , Técnicas de Síntese em Fase Sólida/métodos , Tiazóis/química , Ácidos/química , Sequência de Aminoácidos , Fluorenos/síntese química , Fluorenos/química , Glicopeptídeos/química , Oligopeptídeos/síntese química , Prolina/síntese química , Prolina/química , Compostos de Sulfidrila/química , Tiazóis/síntese química
7.
Org Biomol Chem ; 17(30): 7238-7246, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31328741

RESUMO

The use of peptides as therapeutics has been growing due to their biocompatibility. Solid phase peptide synthesis typically used to access these peptides requires excess reagents and/or microwave irradiation to drive reactions to completion because the reaction medium is heterogeneous. Reported herein is a soluble polynorbornene support containing rink amide attached sites for synthesizing oligopeptides and conotoxins in high purity using only 1.2 to 2 equivalents of coupling reagents. The support can be isolated as a precipitate from the reaction medium by adding ether. The loading capacity of the support can be easily determined by spectroscopy and can also be tuned by varying the monomer ratio. This support is promising for accessing peptides as the methodology uses minimal reagents and by-products can be easily separated.


Assuntos
Amidas/química , Conotoxinas/isolamento & purificação , Oligopeptídeos/isolamento & purificação , Conotoxinas/síntese química , Conotoxinas/química , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Técnicas de Síntese em Fase Sólida , Solubilidade
8.
J Pept Sci ; 25(7): e3192, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31309677

RESUMO

The present study describes modification of asparagine-glycine-arginine (NGR) peptide at N-terminally and C-terminally by introduction of a tridentate chelating scaffold via click chemistry reaction. The N-terminal and C-terminal modified peptides were radiometalated with [99m Tc(CO)3 ]+ precursor. The influence of these moieties at the two termini on the targeting properties of NGR peptide was determined by in vitro cell uptake studies and in vivo biodistribution studies. The two radiolabeled constructs did not exhibit any significant variation in uptake in murine melanoma B16F10 cells during in vitro studies. In vivo studies revealed nearly similar tumor uptake of N-terminally modified peptide construct 5 and C-terminally construct 6 at 2 h p.i. (1.9 ± 0.1 vs 2.4 ± 0.2% ID/g, respectively). The tumor-to-blood (T/B) and tumor-to-liver (T/L) ratios of the two radiometalated peptides were also quite similar. The two constructs cleared from all the major organs (heart, lungs, spleen, stomach, and blood) at 4 h p.i. (<1% ID/g). Blocking studies carried out by coinjection of cCNGRC peptide led to approximately 50% reduction in the tumor uptake at 2 h p.i. This work thus illustrates the possibility of convenient modification/radiometalation of NGR peptide at either N- or C-terminus without hampering tumor targeting and pharmacokinetics.


Assuntos
Monóxido de Carbono/química , Desenho de Fármacos , Oligopeptídeos/síntese química , Compostos Radiofarmacêuticos/química , Tecnécio/química , Animais , Linhagem Celular Tumoral , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Distribuição Tecidual
9.
Carbohydr Res ; 482: 107730, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276881

RESUMO

The convergent synthesis of tetra- and penta-saccharide fragments of the TACA dimeric Lex is described. The synthetic strategy relied on the preparation of a protected GlcNTCA-(1,3)-Gal-(1,4)-GlcNAc trisaccharide diol free at O-3 of both glucosamine residues. Key steps in the preparation of this diol involved glycosylation at O-4 of N-acetylglucosamine using activation of a trichloroacetimidate with BF3·Et2O at 40 °C, removal of the non-reducing end O-3' chloroacetate with thiourea, and glycosylation with a N-trichloroacetamido glucosamine trichloroacetimidate donor. After conversion to the diol acceptor, the trisaccharide was selectively fucosylated at the nonreducing end under NIS/TMSOTf activation, or di-fucosylated under CuBr2/Bu4NBr activation. The protected tetra- and pentasaccharides were then efficiently deprotected under dissolving metal conditions and the nonreducing end glucosamine residues were N-acetylated during the reaction work up. The deprotected compounds will be used as soluble competitors to characterize the epitopes recognized by anti-polymeric Lex antibodies.


Assuntos
Dimerização , Antígenos CD15/química , Oligopeptídeos/química , Oligopeptídeos/síntese química , Técnicas de Química Sintética , Glicosilação
10.
Eur J Med Chem ; 179: 527-536, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276897

RESUMO

New analogs of the endogenous opioid agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) have been obtained by introducing modified tyrosines at the position 1 of the sequence. For all analogs, the cis/trans conformation ratio about the tyramine-Pro amide bond, lipophilicity, receptor affinities, and functional activities, have been determined. Among the novel derivatives, [Dmt(3'-Cl)]1EM-2 (4) stood out for its subnanomolar µ-opioid receptor affinity and potent agonist activity, superior to that of the parent peptide EM-2. Hybrid quantum mechanics/molecular mechanics docking computations supported the cis tyramine-Pro bioactive conformation, and allowed us to analyze the contribution of the substituents of the "message" tyramine to binding, highlighting the role of halogen-bonding in the higher receptor affinity of peptide 4.


Assuntos
Analgésicos Opioides/farmacologia , Teoria da Densidade Funcional , Oligopeptídeos/farmacologia , Receptores Opioides/agonistas , Tirosina/farmacologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Conformação Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Relação Estrutura-Atividade , Tirosina/química
11.
Eur J Med Chem ; 177: 235-246, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31152989

RESUMO

Culicinin D is a 10 amino acid peptaibol containing a rare and synthetically challenging (2S,4S,6R)-AHMOD residue, that exhibits potent antiproliferative activity against MDA-MB-468 cells. An SAR study focusing on replacement of the AHMOD residue was undertaken, culminating in the revelation that a 6-hydroxy or 6-keto substituent was essential to retain potent low nanomolar antiproliferative activity.


Assuntos
Antineoplásicos/farmacologia , Oligopeptídeos/farmacologia , Peptaibols/farmacologia , Substituição de Aminoácidos , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Ácidos Decanoicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Oligopeptídeos/síntese química , Oligopeptídeos/química , Peptaibols/síntese química , Peptaibols/química , Estereoisomerismo , Relação Estrutura-Atividade
12.
Mater Sci Eng C Mater Biol Appl ; 102: 45-52, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147016

RESUMO

Tyrosinase inhibitors could effectively limit the activity of tyrosinase in melanocytes to reduce the excessive synthesis and deposition of melanin. However, low skin permeability and lacking in targeting greatly restricted their application. Herein, ZnO quantum dots were synthesized by gel-sol method and grafted with BQ-788, which have been employed as transdermal and targeting carrier to delivery ellagic acid to melanocytes. Ellagic acid loaded ZnO quantum dots with the size distribution of around 9 nm could targetedly bind to melanocytes and enter the melanocytes by endocytosis within 1 h. The ellagic acid release behavior was controlled by the decreasing of pH via the rapid dissolution of ZnO. When the concentration of BQ-788/EA@ZnO was 12.5 µg/mL, the inhibition rate on tyrosinase activity and melanin deposition were up to 44.23 ±â€¯4.97% and 37.50 ±â€¯5.23%, respectively. In view of their good biocompatibility, they were of great potential in clinically external application for tyrosinase inhibition.


Assuntos
Ácido Elágico/química , Inibidores Enzimáticos/farmacologia , Melanócitos/enzimologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Pontos Quânticos/química , Óxido de Zinco/química , Administração Cutânea , Adulto , Materiais Biocompatíveis/farmacologia , Células Cultivadas , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Humanos , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Monofenol Mono-Oxigenase/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/química , Piperidinas/síntese química , Piperidinas/química , Pontos Quânticos/ultraestrutura , Tirosina/metabolismo , Óxido de Zinco/síntese química
13.
Talanta ; 201: 450-454, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122448

RESUMO

A novel aggregation-induced emission (AIE) probe comprised of a hydrophilic protein kinase specific peptide and a hydrophobic tetraphenylethene (TPE) unit was synthesized through click reaction. The prepared TPE-peptide probe could be completely degraded by carboxypeptidase Y (CPY) to release hydrophobic TPE part, which aggregated in buffer solution and showed strong TPE emission. In the presence of casein kinase (CKII), the phosphorylation of peptide prevented the complete degradation by CPY producing the nonemissive probe. Thus, the developed probe can be used to detect CKII homogeneously and conveniently. This detection process can be finished within 1.5 h with high sensitivity (0.05 mU/µL) and good selectivity. The developed method can also be used to screen protein kinase inhibitor even in a complex biological system.


Assuntos
Técnicas Biossensoriais/métodos , Caseína Quinase II/análise , Ensaios Enzimáticos/métodos , Espectrometria de Fluorescência/métodos , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/química , Caseína Quinase II/química , Catepsina A/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Células HeLa , Humanos , Oligopeptídeos/síntese química , Oligopeptídeos/química , Fosforilação , Inibidores de Proteínas Quinases/química , Proteólise , Triazóis/química
14.
Phys Chem Chem Phys ; 21(22): 11916-11923, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31125036

RESUMO

Peptide structural transformation and aggregation is associated with a large number of outsider aetiology diseases, and it is intrinsically linked to amyloid peptide aggregation. Diphenylalanine self-assembled structures are used as robust minimalist beta amyloids not only to elucidate protein aggregation but also to generate hydrogels. Herein, we employed a neutral model peptide Ac-Phe-Phe-Cys-NH2 (Ac-FFC-NH2) to elucidate the role of intermolecular disulfide bonds in protein fibrillation. The Ac-FFC-NH2 peptide initially self-assembles into nanospheres that evolve to amyloid type fibrils under mild oxidative conditions. Incubation of the peptide in the presence of the chemical reduction agent TCEP inhibits the formation of the fibrils, detecting only spherical nanostructures with no secondary structure. Importantly, we triggered the transformation of the preformed linear straight amyloid fibrils to non-fibrillar structures by TCEP treatment. Under this condition, the amyloid bundles are transformed into rings, which evolve to a new spherical microstructure. We showed that the chemical reduction of intermolecular S-S in internal amyloid sequences might favour the off-path intermediates of amyloid fibril growth, even when the fibrils are formed. Our findings demonstrated that in internal amyloid sequences, the formation of intermolecular S-S promotes the formation of amyloid type fibrils; meanwhile, its reduction stabilises non-fibrillar structures. Altogether, this work provides fundamental understanding at the molecular and supramolecular level, thus facilitating the rational design of therapeutic tools for protein aggregation diseases.


Assuntos
Amiloide/química , Dissulfetos/química , Oligopeptídeos/química , Oligopeptídeos/síntese química , Oxirredução , Multimerização Proteica
15.
Eur J Med Chem ; 176: 105-116, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31100648

RESUMO

Development of peptide-based conjugates for targeted tumour therapy is a current research topic providing new possibilities in cancer treatment. In this study, VHLGYAT heptapeptide selected by phage display technique for HT-29 human colon cancer was investigated as homing peptide for drug delivery. Daunomycin was conjugated to the N-terminus of the peptide directly or through Cathepsin B cleavable spacers. Conjugates showed moderate in vitro cytostatic effect. Therefore, sequence modifications were performed by Ala-scan and positional scanning resulting in conjugates with much higher bioactivity. Conjugates in which Gly was replaced by amino acids with bulky apolaric side chains provided the best efficacy. The influence of the cellular uptake, stability and drug release on the anti-tumour activity was investigated. It was found that mainly the difference in the cellular uptake of the conjugates generated the distinct effect on cell viability. One of the most efficient conjugate Dau = Aoa-LRRY-VHLFYAT-NH2 showed tumour growth inhibition on orthotopically developed HT-29 colon cancer in mice with negligible toxic side effect compared to the free drug. We also indicate that this sequence is not specific to HT-29 cells, but it has a remarkable effect on many other cancer cells. Nevertheless, the Phe-containing conjugate was more active in all cases compared to the conjugate with the parent sequence. The literature data suggested that this sequence is highly overlapped with peptides that recognize Hsp70 membrane bound protein overexpressed in many types of tumours.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Daunorrubicina/análogos & derivados , Daunorrubicina/uso terapêutico , Oligopeptídeos/uso terapêutico , Pró-Fármacos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Catepsina B/metabolismo , Proliferação de Células/efeitos dos fármacos , Técnicas de Visualização da Superfície Celular/métodos , Daunorrubicina/metabolismo , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Células HT29 , Humanos , Camundongos SCID , Oligopeptídeos/síntese química , Oligopeptídeos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Proteólise , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Soft Matter ; 15(20): 4200-4207, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31070656

RESUMO

Herein, we have designed and synthesized a novel forky peptide D3F3 that transforms into a hydrogel through crosslinking induced by ZIs stimuli. We have employed D3F3 as a suitable drug carrier that is conjugated with DOX. Since the concentration of zinc ions necessary for triggering gelation falls into the physiological range present in prostate tissue, while other cationic ions fail to trigger at physiological concentrations, the peptide-based drug delivery system (DDS) is injectable and would achieve prostate tissue-specific self-assembly in situ. The D3F3 hydrogels exhibited an optimal gelation time, satisfactory mechanical strength (can be enhanced after incorporation of DOX) as well as excellent thixotropic properties. The DDS reserved some DOX in the prostate 24 h after the injection, making local sustained release possible. In addition, the peptide materials demonstrated no cytotoxicity against normal fibroblast cells and no damage was observed to the prostate tissue of rats. The drug release followed a non-Fickian diffusion model, with no burst release observed. Importantly, the DOX-hydrogel system exhibited good anti-cancer efficacy when incubated with prostate cancer cells DU-145. Therefore, this study lays the groundwork for the future design of tissue-specific DDSs that are triggered by cationic ions (e.g. zinc ions), and the platform could be further developed to incorporate other potent drugs utilized in the field of prostate cancer therapy, thereby increasing their potency and reducing their side effects.


Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Hidrogéis/química , Oligopeptídeos/síntese química , Neoplasias da Próstata/tratamento farmacológico , Animais , Ácido Aspártico/química , Cátions Bivalentes , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Células NIH 3T3 , Próstata , Zinco/química
17.
Phys Chem Chem Phys ; 21(21): 10879-10883, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-30968092

RESUMO

Self-assembling phenylalanine-based peptides have garnered interest owing to their potential for creating new functional materials. Here, we designed four diastereomers, l-Phe-l-Phe-l-Phe (FFF), d-Phe-l-Phe-l-Phe (fFF), l-Phe-d-Phe-l-Phe (FfF) and l-Phe-l-Phe-d-Phe (FFf), to analyze the effect of the d-isomer on the self-assembly. Using SEM, TG, VCD, and solid-state NMR measurements, we found that only FFf forms a γ-turn conformation and self-assembles into a nanoplate with higher thermal stability. The supramolecular structure of FFf consists of intra- and intermolecular hydrogen bonds and π-π stackings. From our results, we have discovered that FFf forms a new type of self-assembling γ-turn conformation, clarifying the structural role of a d-amino acid residue in supramolecular formation.


Assuntos
Nanoestruturas/química , Oligopeptídeos/síntese química , Ligação de Hidrogênio , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Oligopeptídeos/química , Tamanho da Partícula , Fenilalanina/química , Propriedades de Superfície
18.
Chemphyschem ; 20(11): 1475-1487, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30950574

RESUMO

Specific spin labeling allows the site-selective investigation of biomolecules by EPR and DNP enhanced NMR spectroscopy. A novel spin labeling strategy for commercially available Fmoc-amino acids is developed. In this approach, the PROXYL spin label is covalently attached to the hydroxyl side chain of three amino acids hydroxyproline (Hyp), serine (Ser) and tyrosine (Tyr) by a simple three-step synthesis route. The obtained PROXYL containing building-blocks are N-terminally protected by the Fmoc-protection group, which makes them applicable for the use in solid-phase peptide synthesis (SPPS). This approach allows the insertion of the spin label at any desired position during SPPS, which makes it more versatile than the widely used post synthetic spin labeling strategies. For the final building-blocks, the radical activity is proven by EPR. DNP enhanced solid-state NMR experiments employing these building-blocks in a TCE solution show enhancement factors of up to 26 for 1 H and 13 C (1 H→13 C cross-polarization). To proof the viability of the presented building-blocks for insertion of the spin label during SPPS the penta-peptide Acetyl-Gly-Ser(PROXYL)-Gly-Gly-Gly was synthesized employing the spin labeled Ser building-block. This peptide could successfully be isolated and the spin label activity proved by EPR and DNP NMR measurements, showing enhancement factors of 12.1±0.1 for 1 H and 13.9±0.5 for 13 C (direct polarization).


Assuntos
Aminoácidos/síntese química , Fluorenos/síntese química , Oligopeptídeos/síntese química , Pirrolidinas/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Marcadores de Spin/síntese química , Espectroscopia de Ressonância de Spin Eletrônica , Hidroxiprolina/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Serina/síntese química , Tirosina/síntese química
19.
Molecules ; 24(8)2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-31013889

RESUMO

The five melanocortin receptors (MC1R-MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized as appetite modulating agents, the lack of MC3R-selective agonists has impeded progress in modulating this receptor in vivo. In this study, the (pI)DPhe position of the tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 (an MC3R agonist/MC4R antagonist ligand) was investigated with a library of 12 compounds. The compounds in this library were found to have higher agonist efficacy and potency at the mouse (m) MC3R compared to the MC4R, indicating that the Arg-DPhe motif preferentially activates the mMC3R over the mMC4R. This observation may be used in the design of new MC3R-selective ligands, leading to novel probe and therapeutic lead compounds that will be useful for treating metabolic disorders.


Assuntos
Oligopeptídeos , Receptores de Melanocortina/agonistas , Animais , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Receptores de Melanocortina/genética , Receptores de Melanocortina/metabolismo , Relação Estrutura-Atividade
20.
Org Biomol Chem ; 17(19): 4705-4710, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31020985

RESUMO

A non-internalizing αvß3 integrin ligand was conjugated to the anticancer drug MMAE through a ß-glucuronidase-responsive linker. In the presence of ß-glucuronidase, only the conjugate bearing a PEG4 spacer inhibited the proliferation of integrin-expressing cancer cells at low nanomolar concentrations, indicating important structural requirements for the efficacy of these therapeutics.


Assuntos
Antineoplásicos/farmacologia , Glioblastoma/tratamento farmacológico , Integrina alfaVbeta3/antagonistas & inibidores , Oligopeptídeos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Glucuronidase , Humanos , Integrina alfaVbeta3/química , Integrina alfaVbeta3/metabolismo , Ligantes , Conformação Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Relação Estrutura-Atividade , Vitronectina/antagonistas & inibidores , Vitronectina/química , Vitronectina/metabolismo
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