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1.
Sci Rep ; 9(1): 12903, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501473

RESUMO

In subretinal inflammation, activated mononuclear phagocytes (MP) play a key role in the progression of retinopathies. Little is known about the mechanism involved in the loss of photoreceptors leading to vision impairment. Studying retinal damage induced by photo-oxidative stress, we observed that cluster of differentiation 36 (CD36)-deficient mice featured less subretinal MP accumulation and attenuated photoreceptor degeneration. Moreover, treatment with a CD36-selective azapeptide ligand (MPE-001) reduced subretinal activated MP accumulation in wild type mice and preserved photoreceptor layers and function as assessed by electroretinography in a CD36-dependent manner. The azapeptide modulated the transcriptome of subretinal activated MP by reducing pro-inflammatory markers. In isolated MP, MPE-001 induced dissociation of the CD36-Toll-like receptor 2 (TLR2) oligomeric complex, decreasing nuclear factor-kappa B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. In addition, MPE-001 caused an aerobic metabolic shift in activated MP, involving peroxisome proliferator-activated receptor-γ (PPAR-γ) activation, which in turn mitigated inflammation. Accordingly, PPAR-γ inhibition blocked the cytoprotective effect of MPE-001 on photoreceptor apoptosis elicited by activated MP. By altering activated MP metabolism, MPE-001 decreased immune responses to alleviate subsequent inflammation-dependent neuronal injury characteristic of various vision-threatening retinal disorders.


Assuntos
Antígenos CD36/metabolismo , Metabolismo Energético/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Retinite/etiologia , Retinite/metabolismo , Animais , Biomarcadores , Citocinas/metabolismo , Suscetibilidade a Doenças , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Ligantes , Metaboloma , Metabolômica/métodos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patologia , Ligação Proteica , Retinite/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo
2.
J Med Chem ; 60(22): 9263-9274, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-29028172

RESUMO

Azapeptide analogues of growth hormone releasing peptide-6 (GHRP-6) exhibit promising affinity, selectivity, and modulator activity on the cluster of differentiation 36 receptor (CD36). For example, [A1, azaF4]- and [azaY4]-GHRP-6 (1a and 2b) were previously shown to bind selectively to CD36 and exhibited respectively significant antiangiogenic and slight angiogenic activities in a microvascular sprouting assay using choroid explants. The influences of the 1- and 4-position residues on the affinity, anti-inflammatory, and antiangiogenic activity of these azapeptides have now been studied in detail by the synthesis and analysis of a set of 25 analogues featuring Ala1 or His1 and a variety of aromatic side chains at the aza-amino acid residue in the 4-position. Although their binding affinities differed only by a factor of 17, the analogues exhibited significant differences in ability to modulate production of nitric oxide (NO) in macrophages and choroidal neovascularization.


Assuntos
Inibidores da Angiogênese/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antígenos CD36/metabolismo , Histidina/química , Oligopeptídeos/farmacologia , Fenilalanina/análogos & derivados , Substituição de Aminoácidos , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antígenos CD36/química , Corioide/irrigação sanguínea , Macrófagos/efeitos dos fármacos , Camundongos , Neovascularização Fisiológica/efeitos dos fármacos , Óxido Nítrico/biossíntese , Oligopeptídeos/síntese química , Oligopeptídeos/química , Fenilalanina/química , Relação Estrutura-Atividade
3.
J Am Chem Soc ; 136(18): 6754-62, 2014 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-24725163

RESUMO

The marine environment is a rich source of metabolites with potential therapeutic properties and applications for humans. Here we describe the first isolation, solid-phase total synthesis, and full structural assignment of a new class of cyclodepsipeptides from the Madagascan sponge Ecionemia acervus that shows in vitro cytotoxic activities at submicromolar concentrations. Seven structures belonging to a new family of compounds, given the general name stellatolides, were characterized. The sequence and stereochemistry of all the amino acids in these molecules were established by a combination of spectroscopic analysis, chemical degradation, and derivatization studies. Furthermore, the complete structure of stellatolide A was confirmed by an efficient solid-phase method for the first total synthesis and the full structural assignment of this molecule, including the asymmetric synthesis of the unique ß-hydroxy acid moiety (Z)-3-hydroxy-6,8-dimethylnon-4-enoic acid.


Assuntos
Depsipeptídeos/isolamento & purificação , Poríferos/química , Animais , Depsipeptídeos/síntese química , Depsipeptídeos/química , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray
4.
J Pept Sci ; 19(12): 725-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24203503

RESUMO

Aza-glycinyl dipeptides are useful building blocks for the synthesis of a diverse array of azapeptides. The construction of the aza-glycine residue is however challenging, because of the potential for side reactions, such as those leading to formation of oxadiazalone, hydantoin and symmetric urea by-products. Employing N,N'-disuccinimidyl carbonate to activate benzophenone hydrazone, we have developed a more efficient approach for the synthesis of aza-glycinyl dipeptides. Alkylation of the semicarbazone of the resulting protected aza-glycinyl dipeptides using tetraethylammonium hydroxide and propargyl bromide provided an efficient entry into the aza-propargylglycinyl peptide building blocks, which have served previously in various reactions including Sonogashira cross-couplings, dipolar cycloadditions and intramolecular exo-dig cycloadditions to furnish a variety of azapeptide building blocks.


Assuntos
Compostos Aza/química , Dipeptídeos/síntese química , Glicina/química , Alquilação , Reação de Cicloadição , Peptídeos/síntese química , Succinimidas/química
5.
Nat Commun ; 4: 2352, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23989475

RESUMO

Pipecolidepsin A is a head-to-side-chain cyclodepsipeptide isolated from the marine sponge Homophymia lamellosa. This compound shows relevant cytotoxic activity in three human tumour cell lines and has unique structural features, with an abundance of non-proteinogenic residues, including several intriguing amino acids. Although the moieties present in the structure show high synthetic difficulty, the cornerstone is constituted by the unprecedented and highly hindered γ-branched ß-hydroxy-α-amino acid D-allo-(2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L-(2S,3S,4R)-3,4-dimethylglutamine, (2R,3R,4S)-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, D-allo-Thr and L-pipecolic acid. Here we describe the first total synthesis of a D-allo-AHDMHA-containing peptide, pipecolidepsin A, thus allowing chemical structure validation of the natural product and providing a robust synthetic strategy to access other members of the relevant head-to-side-chain family in a straightforward manner.


Assuntos
Depsipeptídeos/farmacologia , Neoplasias/tratamento farmacológico , Ácidos Pipecólicos/farmacologia , Animais , Linhagem Celular Tumoral , Depsipeptídeos/síntese química , Depsipeptídeos/química , Feminino , Células HT29 , Células Hep G2 , Humanos , Células MCF-7 , Masculino , Ácidos Pipecólicos/síntese química , Ácidos Pipecólicos/química , Poríferos/metabolismo , Relação Estrutura-Atividade
6.
Future Med Chem ; 3(9): 1139-64, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21806378

RESUMO

Azapeptides are peptide analogs in which one or more of the amino residues is replaced by a semicarbazide. This substitution of a nitrogen for the α-carbon center results in conformational restrictions, which bend the peptide about the aza-amino acid residue away from a linear geometry. The resulting azapeptide turn conformations have been observed by x-ray crystallography and spectroscopy, as well as predicted based on computational models. In biologically active peptide analogs, the aza-substitution has led to enhanced activity and selectivity as well as improved properties, such as prolonged duration of action and metabolic stability. In light of these characteristics, azapeptides have found important uses as receptor ligands, enzyme inhibitors, drugs, pro-drugs, probes and imaging agents. Recent improvements in synthetic methods for their procurement have ushered in a new era of azapeptide chemistry. This review aims to provide a historical look at the development of azapeptide science along with a focus on recent developments and perspectives on the future of this useful tool for medicinal chemistry.


Assuntos
Compostos Aza/uso terapêutico , Peptídeos/uso terapêutico , Semicarbazidas/uso terapêutico , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Conformação Molecular , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia , Semicarbazidas/síntese química , Semicarbazidas/química , Semicarbazidas/farmacologia , Relação Estrutura-Atividade
7.
J Pept Sci ; 16(12): 675-8, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20853309

RESUMO

CM resin is a totally PEG-based resin, made exclusively from primary ether bonds and therefore highly chemically stable. Compared to other PEG resins, it exhibits good loading and is user friendly because of its free-flowing form upon drying. It shows improved performance over PS resins for the preparation of hydrophobic, highly structured poly-Arg peptides. In combination with ψPros, it allows the synthesis of small proteins such as the chemokine RANTES. Like other PEG-based resins, CM resin swells well in biocompatible solvents such as water, thereby allowing on-bead screening. Furthermore, the high loading of this resin permits the use of a tiny quarter of a bead as a microreactor for HPLC and MALDI-TOF analysis, thus further extending its applications in the field of combinatorial chemistry.


Assuntos
Técnicas de Química Combinatória , Peptídeos/química , Polietilenoglicóis/química , Resinas Sintéticas/química , Arginina/química , Cromatografia Líquida de Alta Pressão , Estrutura Molecular , Peptídeos/síntese química , Resinas Sintéticas/síntese química
8.
Biopolymers ; 92(6): 565-72, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19802821

RESUMO

Thymosin alpha1 is a 28-amino acid acetylated peptide used for the treatment of hepatitis B and C. This peptide has a difficult sequence because of the presence of consecutive beta-branched amino acids and shows a tendency to form beta-sheet structures, partly as a result of the many protecting groups required to assemble the peptide (up to 20 side-chain protecting groups). Consequently, its synthesis has been generally achieved by convergent solution chemistry. Here we report a straightforward stepwise solid-phase synthesis on a polyethylene glycol solid-support that enables the scaling-up of this key therapeutic peptide.


Assuntos
Antineoplásicos/síntese química , Polietilenoglicóis/química , Timosina/análogos & derivados , Acetilação , Antineoplásicos/química , Humanos , Estrutura Secundária de Proteína , Timalfasina , Timosina/síntese química , Timosina/química
9.
J Comb Chem ; 8(2): 213-20, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16529516

RESUMO

CM (ChemMatrix) resin is a new, totally poly(ethylene glycol) (PEG)-based resin, made exclusively from primary ether bonds and, therefore, highly chemically stable. It exhibits good loading and is user-friendly because of its free-flowing form upon drying. It performs excellently for the preparation of hydrophobic, highly structured, and poly-Arg peptides, as compared to polystyrene (PS) resins. In the most striking example, stepwise solid-phase assembly of the highly complex beta-amyloid (1-42) peptide resulted in a crude material of 91% purity. In contrast, literature procedures using PS or PEG-PS-based resins for this peptide required convergent approaches, additional time-consuming steps, or both. In addition to the difficulties of its synthesis, characterization of the beta-amyloid (1-42) peptide as a monomer is also a challenge, and methods for characterization by HPLC and MALDI-TOF have also been developed.


Assuntos
Peptídeos beta-Amiloides/síntese química , Fragmentos de Peptídeos/síntese química , Peptídeos/síntese química , Polietilenoglicóis , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Resinas Sintéticas , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrofotometria Infravermelho
10.
J Org Chem ; 70(23): 9529-37, 2005 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-16268629

RESUMO

[Reaction: see text]. A variety of 5-chloro-2(H)-1,4-oxazin-2-ones bearing a range of substituents at their 3- and 6-positions undergo Diels-Alder cycloaddition as a 2-azadiene component with electron-rich, electron-deficient, and electron-neutral dienophiles. These reactions proceed with moderate regio- and stereoselectivity to afford relatively stable and readily isolable bridged bicyclic lactone cycloadducts. Chemical manipulation of these cycloadducts affords highly substituted and functionally rich piperidines. The regio- and stereochemical preferences of the cycloadditions of 5-chloro-2(H)-1,4-oxazin-2-ones are investigated computationally using density functional theory (B3LYP/6-31G).

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