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Carbohydr Res ; 498: 108155, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33010570


The synthesis of MUC1 glycopeptides bearing modified tumor-associated carbohydrate antigens (TACAs) represents an effective strategy to develop potential antitumor vaccines that trigger strong immune response. In this context, we present herein the multistep synthesis of the triazole glycosyl amino acid Neu5Ac-α/ß2-triazole-6-ßGalNAc-ThrOH 1 as STn antigen analog, along with its assembly on the corresponding MUC1 peptide to give NAcProAsp [Neu5Acα/ß2-triazole-6-ßGalNAc]ThrArgProGlyOH 2. Despite interacting differently with SM3 monoclonal antibody, as shown by molecular dynamic simulations, this unnatural triazole glycopeptide may represent a promising candidate for cancer immunotherapy.

Antígenos Glicosídicos Associados a Tumores/química , Glicopeptídeos/química , Glicopeptídeos/síntese química , Mucina-1/química , Triazóis/química , Técnicas de Química Sintética
Free Radic Biol Med ; 115: 421-435, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29248721


In this study, we report the ability of a set of eight 3-phenylcoumarin derivatives bearing 6,7- or 5,7-dihydroxyl groups, free or acetylated, bound to the benzopyrone moiety, to modulate the effector functions of human neutrophils. In general, (i) 6,7-disubstituted compounds (5, 6, 19, 20) downmodulated the Fcγ receptor-mediated neutrophil oxidative metabolism more strongly than 5,7-disubstituted compounds (21, 22, 23, 24), and (ii) hydroxylated compounds (5, 19, 21, 23) downmodulated this neutrophil function more effectively than their acetylated counterparts (6, 20, 22, 24, respectively). Compounds 5 (6,7-dihydroxy-3-[3',4'-methylenedioxyphenyl]-coumarin) and 19 (6,7-dihydroxy-3-[3',4'-dihydroxyphenyl]-coumarin) effectively downmodulated the neutrophil oxidative metabolism elicited via Fcγ and/or complement receptors. Compound 5 also downmodulated the immune complex-stimulated phagocytosis, degranulation of elastase, and production and release of neutrophil extracellular traps, as well as the human neutrophil chemotaxis towards n-formyl-methionyl-leucyl-phenylalanine, without altering the expression level of formyl peptide receptor type 1. Both compounds 5 and 19 did not impair the neutrophil capacity to recognize and kill Candida albicans. Docking calculations revealed that compounds 5 and 19 directly interacted with three catalytic residues - Gln-91, His-95, and Arg-239 - inside the myeloperoxidase active site. Together, these findings indicate that (i) inhibition of reactive oxygen species generation and degranulation of elastase are closely associated with downmodulation of release of neutrophil extracellular traps; and (ii) compound 5 can be a prototype for the development of novel immunomodulating drugs to treat immune complex-mediated inflammatory diseases.

Anti-Inflamatórios/farmacologia , Cumarínicos/farmacologia , Armadilhas Extracelulares/metabolismo , Neutrófilos/fisiologia , Elastase Pancreática/metabolismo , Receptores de Complemento/metabolismo , Receptores de IgG/metabolismo , Anti-Inflamatórios/química , Células Cultivadas , Cumarínicos/química , Humanos , Imunomodulação , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Fagocitose , Espécies Reativas de Oxigênio/metabolismo
J Pharm Pharmacol ; 69(12): 1829-1845, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28994118


OBJECTIVES: To examine whether the hydroalcoholic extract from Baccharis dracunculifolia leaves (BdE) modulates the human neutrophil oxidative metabolism, degranulation, phagocytosis and microbial killing capacity. METHODS: In-vitro assays based on chemiluminescence, spectrophotometry, flow cytometry and polarimetry were used, as well as docking calculations. KEY FINDINGS: At concentrations that effectively suppressed the neutrophil oxidative metabolism elicited by soluble and particulate stimuli (<10 µg/ml), without clear signs of cytotoxicity, BdE (1) inhibited NADPH oxidase and myeloperoxidase activity; (2) scavenged H2 O2 and HOCl; (3) weakly inhibited phagocytosis; and (4) did not affect neutrophil degranulation and microbial killing capacity, the expression levels of TLR2, TLR4, FcγRIIa, FcγRIIIb and CR3 and the activity of elastase and lysozyme. Caffeic acid, one of the major B. dracunculifolia secondary metabolites, did not inhibit phagocytosis but interfered in the myeloperoxidase-H2 O2 -HOCl system by scavenging H2 O2 and HOCl, and interacting with the catalytic residues His-95, Arg-239 and Gln-91. CONCLUSIONS: BdE selectively modulates the effector functions of human neutrophils, inhibits the activity of key enzymes and scavenges physiological oxidant species. Caffeic acid contributes to lower the levels of oxidant species. Our findings help to unravel the mechanisms by which these natural products exert immunomodulatory action towards neutrophils.

Baccharis/química , Fatores Imunológicos/farmacologia , Neutrófilos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Adulto , Ácidos Cafeicos/isolamento & purificação , Ácidos Cafeicos/farmacologia , Citometria de Fluxo , Sequestradores de Radicais Livres/isolamento & purificação , Sequestradores de Radicais Livres/farmacologia , Humanos , Fatores Imunológicos/isolamento & purificação , Luminescência , Neutrófilos/metabolismo , Fagocitose/efeitos dos fármacos , Folhas de Planta , Espectrofotometria
Proteins ; 82(9): 1850-68, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24677212


The protein structure prediction problem continues to elude scientists. Despite the introduction of many methods, only modest gains were made over the last decade for certain classes of prediction targets. To address this challenge, a social-media based worldwide collaborative effort, named WeFold, was undertaken by 13 labs. During the collaboration, the laboratories were simultaneously competing with each other. Here, we present the first attempt at "coopetition" in scientific research applied to the protein structure prediction and refinement problems. The coopetition was possible by allowing the participating labs to contribute different components of their protein structure prediction pipelines and create new hybrid pipelines that they tested during CASP10. This manuscript describes both successes and areas needing improvement as identified throughout the first WeFold experiment and discusses the efforts that are underway to advance this initiative. A footprint of all contributions and structures are publicly accessible at

Biologia Computacional/métodos , Simulação por Computador , Comportamento Cooperativo , Estrutura Terciária de Proteína , Proteínas/ultraestrutura , Humanos , Modelos Moleculares , Projetos de Pesquisa , Jogos de Vídeo