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1.
Sci Immunol ; 9(95): eadn0126, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38728413

RESUMO

MR1T cells are a recently found class of T cells that recognize antigens presented by the major histocompatibility complex-I-related molecule MR1 in the absence of microbial infection. The nature of the self-antigens that stimulate MR1T cells remains unclear, hampering our understanding of their physiological role and therapeutic potential. By combining genetic, pharmacological, and biochemical approaches, we found that carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Stimulatory compounds formed by carbonyl adducts of nucleobases were detected within MR1 molecules produced by tumor cells, and their abundance and antigenicity were enhanced by drugs that induce carbonyl accumulation. Our data reveal carbonyl-nucleobase adducts as MR1T cell antigens. Recognizing cells under carbonyl stress allows MR1T cells to monitor cellular metabolic changes with physiological and therapeutic implications.


Assuntos
Antígenos de Histocompatibilidade Classe I , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Antígenos de Histocompatibilidade Menor/metabolismo , Antígenos de Histocompatibilidade Menor/imunologia , Animais , Ativação Linfocitária/imunologia , Camundongos , Linfócitos T/imunologia
2.
J Am Chem Soc ; 146(7): 4605-4619, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38334415

RESUMO

Development of first-row transition metal complexes with similar luminescence and photoredox properties as widely used RuII polypyridines is attractive because metals from the first transition series are comparatively abundant and inexpensive. The weaker ligand field experienced by the valence d-electrons of first-row transition metals challenges the installation of the same types of metal-to-ligand charge transfer (MLCT) excited states as in precious metal complexes, due to rapid population of energetically lower-lying metal-centered (MC) states. In a family of isostructural tris(diisocyanide) complexes of the 3d6 metals Cr0, MnI, and FeII, the increasing effective nuclear charge and ligand field strength allow us to control the energetic order between the 3MLCT and 3MC states, whereas pyrene decoration of the isocyanide ligand framework provides control over intraligand (ILPyr) states. The chromium(0) complex shows red 3MLCT phosphorescence because all other excited states are higher in energy. In the manganese(I) complex, a microsecond-lived dark 3ILPyr state, reminiscent of the types of electronic states encountered in many polyaromatic hydrocarbon compounds, is the lowest and becomes photoactive. In the iron(II) complex, the lowest MLCT state has shifted to so much higher energy that 1ILPyr fluorescence occurs, in parallel to other excited-state deactivation pathways. Our combined synthetic-spectroscopic-theoretical study provides unprecedented insights into how effective nuclear charge, ligand field strength, and ligand π-conjugation affect the energetic order between MLCT and ligand-based excited states, and under what circumstances these individual states become luminescent and exploitable in photochemistry. Such insights are the key to further developments of luminescent and photoredox-active first-row transition metal complexes.

3.
Nat Commun ; 14(1): 7823, 2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-38016954

RESUMO

Ultra-tight binding is usually observed for proteins associating with rigidified molecules. Previously, we demonstrated that femtomolar binders derived from the Armadillo repeat proteins (ArmRPs) can be designed to interact very tightly with fully flexible peptides. Here we show for ArmRPs with four and seven sequence-identical internal repeats that the peptide-ArmRP complexes display conformational dynamics. These dynamics stem from transient breakages of individual protein-residue contacts that are unrelated to overall unbinding. The labile contacts involve electrostatic interactions. We speculate that these dynamics allow attaining very high binding affinities, since they reduce entropic losses. Importantly, only NMR techniques can pick up these local events by directly detecting conformational exchange processes without complications from changes in solvent entropy. Furthermore, we demonstrate that the interaction surface of the repeat protein regularizes upon peptide binding to become more compatible with the peptide geometry. These results provide novel design principles for ultra-tight binders.


Assuntos
Proteínas de Transporte , Peptídeos , Proteínas de Transporte/metabolismo , Peptídeos/química , Proteínas/metabolismo , Proteínas do Domínio Armadillo/metabolismo , Entropia , Ligação Proteica , Conformação Proteica
4.
Nat Chem ; 15(12): 1730-1736, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37580444

RESUMO

Coordination complexes of precious metals with the d6 valence electron configuration such as Ru(II), Os(II) and Ir(III) are used for lighting applications, solar energy conversion and photocatalysis. Until now, d6 complexes made from abundant first-row transition metals with competitive photophysical and photochemical properties have been elusive. While previous research efforts focused mostly on Fe(II), we disclose that isoelectronic Cr(0) gives access to higher photoluminescence quantum yields and excited-state lifetimes when compared with any other first-row d6 metal complex reported so far. The luminescence behaviour of the metal-to-ligand charge transfer excited states of these Cr(0) complexes is competitive with Os(II) polypyridines. With these Cr(0) complexes, the metal-to-ligand charge transfer states of first-row d6 metal complexes become exploitable in photoredox catalysis, and benchmark chemical reductions proceed efficiently under low-energy red illumination. Here we demonstrate that appropriate molecular design strategies open up new perspectives for photophysics and photochemistry with abundant first-row d6 metals.

5.
Inorg Chem ; 61(27): 10533-10547, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35768069

RESUMO

Recently reported manganese(I) complexes with chelating arylisocyanide ligands exhibit luminescent metal-to-ligand charge-transfer (MLCT) excited states, similar to ruthenium(II) polypyridine complexes with the same d6 valence electron configuration used for many different applications in photophysics and photochemistry. However, chelating arylisocyanide ligands require substantial synthetic effort, and therefore it seemed attractive to explore the possibility of using more readily accessible monodentate arylisocyanides instead. Here, we synthesized the new Mn(I) complex [Mn(CNdippPhOMe2)6]PF6 with the known ligand CNdippPhOMe2 = 4-(3,5-dimethoxyphenyl)-2,6-diisopropylphenylisocyanide. This complex was investigated by NMR spectroscopy, single-crystal structure analysis, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) measurements, IR spectroscopy supported by density functional theory (DFT) calculations, cyclic voltammetry, and time-resolved as well as steady-state UV-vis absorption spectroscopy. The key finding is that the new Mn(I) complex is nonluminescent and instead undergoes arylisocyanide ligand loss during continuous visible laser irradiation into ligand-centered and charge-transfer absorption bands, presumably owed to the population of dissociative d-d excited states. Thus, it seems that chelating bi- or tridentate binding motifs are essential for obtaining emissive MLCT excited states in manganese(I) arylisocyanides. Our work contributes to understanding the basic properties of photoactive first-row transition metal complexes and could help advance the search for alternatives to precious metal-based luminophores, photocatalysts, and sensors.

6.
J Am Chem Soc ; 143(38): 15800-15811, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34516734

RESUMO

There is a long-standing interest in iron(II) complexes that emit from metal-to-ligand charge transfer (MLCT) excited states, analogous to ruthenium(II) polypyridines. The 3d6 electrons of iron(II) are exposed to a relatively weak ligand field, rendering nonradiative relaxation of MLCT states via metal-centered excited states undesirably efficient. For isoelectronic chromium(0), chelating diisocyanide ligands recently provided access to very weak MLCT emission in solution at room temperature. Here, we present a concept that boosts the luminescence quantum yield of a chromium(0) isocyanide complex by nearly 2 orders of magnitude, accompanied by a significant increase of the MLCT lifetime. Pyrene units in the diisocyanide ligand backbone lead to an enlarged π-conjugation system and to a strongly delocalized MLCT state, from which nonradiative relaxation is less dominant despite a sizable redshift of the emission. While the pyrene moiety is electronically coupled to the core of the chromium(0) complex in the excited state, UV-vis absorption and 2D NMR spectroscopy show that this is not the case in the ground state. Luminescence lifetimes and quantum yields for our pyrenyl-decorated chromium(0) complex exhibit an unusual bell-shaped dependence on solvent polarity, indicative of two counteracting effects governing the MLCT deactivation. These two effects are identified as predominant deactivation either through an energetically nearby lying metal-centered state in the most apolar solvents, or alternatively via direct nonradiative relaxation to the ground state following the energy gap law in more polar solvents. This is the first example of a 3d6 MLCT emitter to benefit from an increased π-conjugation network.

7.
Nat Commun ; 12(1): 4844, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381053

RESUMO

Acute leukemia relapsing after chemotherapy plus allogeneic hematopoietic stem cell transplantation can be treated with donor-derived T cells, but this is hampered by the need for donor/recipient MHC-matching and often results in graft-versus-host disease, prompting the search for new donor-unrestricted strategies targeting malignant cells. Leukemia blasts express CD1c antigen-presenting molecules, which are identical in all individuals and expressed only by mature leukocytes, and are recognized by T cell clones specific for the CD1c-restricted leukemia-associated methyl-lysophosphatidic acid (mLPA) lipid antigen. Here, we show that human T cells engineered to express an mLPA-specific TCR, target diverse CD1c-expressing leukemia blasts in vitro and significantly delay the progression of three models of leukemia xenograft in NSG mice, an effect that is boosted by mLPA-cellular immunization. These results highlight a strategy to redirect T cells against leukemia via transfer of a lipid-specific TCR that could be used across MHC barriers with reduced risk of graft-versus-host disease.


Assuntos
Antígenos CD1/imunologia , Glicoproteínas/imunologia , Leucemia/imunologia , Lisofosfolipídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Doadores de Tecidos , Animais , Apresentação de Antígeno , Antígenos CD1/metabolismo , Glicoproteínas/metabolismo , Humanos , Imunoterapia Adotiva , Leucemia/metabolismo , Leucemia/terapia , Ativação Linfocitária , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Chemistry ; 27(20): 6295-6307, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33502051

RESUMO

The novel diacetylene bridged terphenylic macrocycle 1 is presented and discussed in the context of rotationally restricted "Geländer" oligomers. The 1,4-bis(phenylbuta-1,3-diyn-1-yl) benzene bridge of diacetylene 1 is significantly longer than its terphenyl backbone, forcing the bridge to bend around the central pylon. The synthesis of molecule 1 is based to a large extent on acetylene scaffolding strategies, profiting from orthogonal alkyne protection groups to close both macrocyclic subunits by oxidative acetylene coupling sequentially. The spatial arrangement and the dynamic enantiomerization process of the bicyclic target structure 1 are analyzed. In-depth NMR investigations not only reveal an unexpected spatial arrangement with both oligomer strands bent alongside the backbone, but also display the limited stability of the model compound in the presence of molecular oxygen.

9.
Chem Commun (Camb) ; 56(84): 12861-12864, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-32969418

RESUMO

Herein, a novel and rationally designed ortho-substituted pyridine activator is reported that reacts rapidly and selectively with cysteine thiols. It forms reduction-stable conjugates and induces large pseudocontact shifts, residual dipolar couplings and paramagnetic relaxation enhancement on both ubiquitin S57C and human carbonic anhydrase II S50C constructs under physiological conditions.


Assuntos
Anidrase Carbônica II/química , Quelantes/química , Complexos de Coordenação/química , Indicadores e Reagentes/química , Elementos da Série dos Lantanídeos/química , Ressonância Magnética Nuclear Biomolecular/métodos , Alquilação , Anisotropia , Cisteína/química , Humanos , Modelos Moleculares , Oxirredução , Conformação Proteica , Piridinas/química , Compostos de Sulfidrila/química , Ubiquitina/química
10.
Chemistry ; 26(66): 15298-15312, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-32852800

RESUMO

This article provides a detailed report of our efforts to synthesize the dithiodiketopiperazine (DTP) natural products (-)-epicoccin G and (-)-rostratin A using a double C(sp3 )-H activation strategy. The strategy's viability was first established on a model system lacking the C8/C8' alcohols. Then, an efficient stereoselective route including an organocatalytic epoxidation was secured to access a key bis-triflate substrate. This bis-triflate served as the functional handles for the key transformation of the synthesis: a double C(sp3 )-H activation. The successful double activation opened access to a common intermediate for both natural products in high overall yield and on a multigram scale. After several unsuccessful attempts, this intermediate was efficiently converted to (-)-epicoccin G and to the more challenging (-)-rostratin A via suitable oxidation/reduction and protecting group sequences, and via a final sulfuration that occurred in good yield and high diastereoselectivity. These efforts culminated in the synthesis of (-)-epicoccin G and (-)-rostratin A in high overall yields (19.6 % over 14 steps and 12.7 % over 17 steps, respectively), with the latter being obtained on a 500 mg scale. Toxicity assessments of these natural products and several analogues (including the newly synthesized epicoccin K) in the leukemia cell line K562 confirmed the importance of the disulfide bridge for activity and identified dianhydrorostratin A as a 20x more potent analogue.


Assuntos
Produtos Biológicos , Piperazinas/síntese química , Oxirredução , Piperazinas/química , Estereoisomerismo
11.
Inorg Chem ; 59(15): 10907-10919, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32658468

RESUMO

With a half-life of 7.45 days, silver-111 (ßmax 1.04 MeV, Eγ 245.4 keV [Iγ 1.24%], Eγ 342.1 keV [Iγ 6.7%]) is a promising candidate for targeted cancer therapy with ß- emitters as well as for associated SPECT imaging. For its clinical use, the development of suitable ligands that form sufficiently stable Ag+-complexes in vivo is required. In this work, the following sulfur-containing derivatives of tetraazacyclododecane (cyclen) have been considered as potential chelators for silver-111: 1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S), (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S4Me), 1,4,7-tris(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris(2-(methylsulfanyl)ethyl)-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis(2-(methylsulfanyl)ethyl)-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). Natural Ag+ was used in pH/Ag-potentiometric and UV-vis spectrophotometric studies to determine the metal speciation existing in aqueous NaNO3 0.15 M at 25 °C and the equilibrium constants of the complexes, whereas NMR and DFT calculations gave structural insights. Overall results indicated that sulfide pendant arms coordinate Ag+ allowing the formation of very stable complexes, both at acidic and physiological pH. Furthermore, radiolabeling, stability in saline phosphate buffer, and metal-competition experiments using the two ligands forming the strongest complexes, DO4S and DO4S4Me, were carried out with [111Ag]Ag+ and promising results were obtained.


Assuntos
Complexos de Coordenação/química , Ciclamos/química , Compostos Radiofarmacêuticos/química , Prata/química , Sulfetos/química , Teoria da Densidade Funcional , Concentração de Íons de Hidrogênio , Ligantes , Estrutura Molecular , Termodinâmica
12.
Angew Chem Int Ed Engl ; 59(37): 15947-15952, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32412664

RESUMO

The coordination sphere of the Fe(II) terpyridine complex 1 is rigidified by fourfold interlinking of both terpyridine ligands. Profiting from an octa-aldehyde precursor complex, the ideal dimensions of the interlinking structures are determined by reversible Schiff-base formation, before irreversible Wittig olefination provided the rigidified complex. Reversed-phase HPLC enables the isolation of the all-trans isomer of the Fe(II) terpyridine complex 1, which is fully characterized. While temperature independent low-spin states were recorded with superconducting quantum interference device (SQUID) measurements for both, the open precursor 8 and the interlinked complex 1, evidence of the increased rigidity of the ligand sphere in 1 was provided by proton T2 relaxation NMR experiments. The ligand sphere fixation in the macrocyclized complex 1 even reaches a level resisting substantial deformation upon deposition on an Au(111) surface, as demonstrated by its pristine form in a low temperature ultra-high vacuum scanning tunneling microscope experiment.

13.
J Med Chem ; 63(9): 4484-4495, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302139

RESUMO

MG11 is a truncated analog of minigastrin, a peptide with high affinity and specificity toward the cholecystokinin-2 receptor (CCK2R), which is overexpressed by different tumors. Thus, radiolabeled MG11 derivatives have great potential for use in cancer diagnosis and therapy. A drawback of MG11 is its fast degradation by proteases, leading to moderate tumor uptake in vivo. We introduced 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres to replace labile amide bonds of the peptide. The "triazole scan" yielded peptidomimetics with improved resistance to enzymatic degradation and/or enhanced affinity toward the CCK2R. Remarkably, our lead compound achieved a 10-fold increase in receptor affinity, resulting in a 2.6-fold improved tumor uptake in vivo. Modeling of the ligand-CCK2R complex suggests that an additional cation-π interaction of the aromatic triazole moiety with the Arg356 residue of the receptor is accountable for these observations. We show for the first time that the amide-to-triazole substitution strategy offers new opportunities in drug development that go beyond the metabolic stabilization of bioactive peptides.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Conformação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
14.
Chem Sci ; 10(29): 7049-7058, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31588272

RESUMO

The formylglycine generating enzyme (FGE) catalyzes oxidative conversion of specific peptidyl-cysteine residues to formylglycine. FGE mediates O2-activation and hydrogen-atom abstraction in an active site that contains Cu(i) coordinated to two cysteine residues. Similar coordination geometries are common among copper-sensing transcription factors and copper-chaperone but are unprecedented among copper-dependent oxidases. To examine the mechanism of this unusual catalyst we determined the 1.04 Å structure of FGE from Thermomonospora curvata in complex with copper and a cysteine-containing peptide substrate. This structure unveils a network of four crystallographic waters and two active site residues that form a highly acidic O2-binding pocket juxtaposed to the trigonal planar tris-cysteine coordinated Cu(i) center. Comparison with structures of FGE in complex with Ag(i) and Cd(ii) combined with evidence from NMR spectroscopy and kinetic observations highlight several structural changes that are induced by substrate binding and prime the enzyme for O2-binding and subsequent activation.

15.
Chem Sci ; 10(19): 5064-5072, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31183057

RESUMO

Unraveling the native structure of protein-ligand complexes in solution enables rational drug design. We report here the use of 19F pseudocontact shift (PCS) NMR as a method to determine fluorine positions of high affinity ligands bound within the drug target human carbonic anhydrase II with high accuracy. Three different ligands were localized within the protein by analysis of the obtained PCS from simple one-dimensional 19F spectra with an accuracy of up to 0.8 Å. In order to validate the PCS, four to five independent magnetic susceptibility tensors induced by lanthanide chelating tags bound site-specifically to single cysteine mutants were refined. Least-squares minimization and a Monte-Carlo approach allowed the assessment of experimental errors on the intersection of the corresponding four to five PCS isosurfaces. By defining an angle score that reflects the relative isosurface orientation for different tensor combinations, it was established that the ligand can be localized accurately using only three tensors, if the isosurfaces are close to orthogonal. For two out of three ligands, the determined position closely matched the X-ray coordinates. Our results for the third ligand suggest, in accordance with previously reported ab initio calculations, a rotated position for the difluorophenyl substituent, enabling a favorable interaction with Phe-131. The lanthanide-fluorine distance varied between 22 and 38 Å and induced 19F PCS ranged from 0.078 to 0.409 ppm, averaging to 0.213 ppm. Accordingly, even longer metal-fluorine distances will lead to meaningful PCS, rendering the investigation of protein-ligand complexes significantly larger than 30 kDa feasible.

16.
Bioconjug Chem ; 29(10): 3344-3351, 2018 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-30160477

RESUMO

Lanthanide chelating tags (LCTs) have been used with great success for determining structures and interactions of proteins and other biological macromolecules. Recently LCTs have also been used for in-cell NMR spectroscopy, but the bottleneck especially for demanding applications like pseudocontact shift (PCS) NMR is the sparse availability of suitable tags that allow for site-selective, rigid, irreversible, fast, and quantitative conjugation of chelated paramagnetic lanthanide ions to proteins via reduction stable bonds. We report here several such tags and focus on a new pyridine thiazole derivate of DOTA, that combines high affinity, rigidity, and selectivity with unprecedented tagging properties. The conjugation to the cysteine thiol of the protein results in a reductively stable thioether bond and proceeds virtually quantitatively in less than 30 min at 100 µM protein concentration, ambient temperature, and neutral pH. Upon conjugation of the new tag to two single cysteine mutants of ubiquitin and a single cysteine mutant of human carbonic anhydrase type II (30 kDa) only one stereoisomer is formed (square antiprismatic coordination, Λ(δδδδ)) and large to very large pseudocontact shifts as well as large residual dipolar couplings (RDCs) are observed by NMR spectroscopy. The PCS and RDC show excellent agreement with the solid state structure of the proteins. We believe that the pyridine thiazole moiety reported here has the potential to serve as a thiole reactive group in various conjugation applications; furthermore, its terbium complex shows strong photoluminescence upon irradiation and may thus serve as a donor group for Förster resonance energy transfer spectroscopy.


Assuntos
Quelantes/química , Elementos da Série dos Lantanídeos/química , Ressonância Magnética Nuclear Biomolecular/métodos , Proteínas/química , Luminescência , Conformação Proteica
17.
18.
Chem Commun (Camb) ; 50(78): 11523-5, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25132321

RESUMO

(89)Zr-based imaging agents hold great promise as novel radio-tracers in nuclear medicine. However, insufficient stability of currently used radiometal complexes in vivo is a safety concern for clinical applications. We herein report the first octadentate bifunctional chelating agent for the development of (89)Zr-labelled (bio)conjugates with improved stability.


Assuntos
Quelantes/química , Complexos de Coordenação/química , Sondas Moleculares/química , Zircônio/química , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , Desferroxamina/química , Humanos , Conformação Molecular , Sondas Moleculares/síntese química , Sondas Moleculares/metabolismo , Peptídeos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo
19.
Chem Commun (Camb) ; 50(62): 8499-502, 2014 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-24946836

RESUMO

We describe a simple method for the direct modification of nucleobases in cyclic purine dinucleotides, important signalling molecules in both prokaryotes and eukaryotes. The method tolerates all members of the cyclic dinucleotide family and could be used to modulate their function or introduce useful side-chains such as fluorophores and photo-crosslinking groups.


Assuntos
Fosfatos de Dinucleosídeos/química , Metano/análogos & derivados , Purinas/química , Rênio/química , Catálise , Metano/química
20.
J Exp Med ; 211(7): 1363-77, 2014 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-24935257

RESUMO

T cells that recognize self-lipids presented by CD1c are frequent in the peripheral blood of healthy individuals and kill transformed hematopoietic cells, but little is known about their antigen specificity and potential antileukemia effects. We report that CD1c self-reactive T cells recognize a novel class of self-lipids, identified as methyl-lysophosphatidic acids (mLPAs), which are accumulated in leukemia cells. Primary acute myeloid and B cell acute leukemia blasts express CD1 molecules. mLPA-specific T cells efficiently kill CD1c(+) acute leukemia cells, poorly recognize nontransformed CD1c-expressing cells, and protect immunodeficient mice against CD1c(+) human leukemia cells. The identification of immunogenic self-lipid antigens accumulated in leukemia cells and the observed leukemia control by lipid-specific T cells in vivo provide a new conceptual framework for leukemia immune surveillance and possible immunotherapy.


Assuntos
Antígenos CD1/imunologia , Autoantígenos/imunologia , Crise Blástica/imunologia , Glicoproteínas/imunologia , Vigilância Imunológica , Leucemia Mieloide Aguda/imunologia , Lisofosfolipídeos/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Linfócitos T/imunologia , Adolescente , Animais , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Antígenos CD1/genética , Autoantígenos/genética , Crise Blástica/genética , Crise Blástica/patologia , Criança , Pré-Escolar , Feminino , Regulação Leucêmica da Expressão Gênica/genética , Regulação Leucêmica da Expressão Gênica/imunologia , Glicoproteínas/genética , Humanos , Células Jurkat , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Lisofosfolipídeos/genética , Masculino , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Linfócitos T/patologia
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