RESUMO
Planet Earth is warming at an unprecedented rate and our future is now assured to be shaped by the consequences of more frequent hot days and extreme heat. Humans will need to adapt both behaviorally and physiologically to thrive in a hotter climate. From a physiological perspective, countless studies have shown that human heat acclimation increases thermoeffector output (i.e., sweating and skin blood flow) and lowers cardiovascular strain (i.e., heart rate) during heat stress. However, the mechanisms mediating these adaptations remain understudied. Furthermore, several possible benefits of heat acclimation for other systems and functions involved in maintaining health and performance during heat stress remain to be elucidated. This review summarizes recent advances in human heat acclimation, with emphasis on recent studies that (1) advanced our understanding of the mechanisms mediating improved thermoeffector output and (2) investigated adaptations that go beyond those classically associated with heat acclimation. We highlight that these studies have contributed to a better understanding of the integrated physiological responses underlying human heat acclimation while leaving key unanswered questions that will need to be addressed in the future.
Assuntos
Aclimatação , Regulação da Temperatura Corporal , Humanos , Regulação da Temperatura Corporal/fisiologia , Aclimatação/fisiologia , Temperatura Alta , Adaptação Fisiológica/fisiologia , SudoreseRESUMO
Artificial water channels (AWCs) are known to selectively transport water, with ion exclusion. Similarly to natural porins, AWCs encapsulate water wires or clusters, offering continuous and iterative H-bonding that plays a vital role in their stabilization. Herein, we report octyl-ureido-polyol AWCs capable of self-assembly into hydrophilic hydroxy channels. Variants of ethanol, propanediol, and trimethanol are used as head groups to modulate the water transport permeabilities, with rejection of ions. The hydroxy channels achieve a single-channel permeability of 2.33 × 108 water molecules per second, which is within the same order of magnitude as the transport rates for aquaporins. Depending on their concentration in the membrane, adaptive channels are observed in the membrane. Over increased concentrations, a significant shift occurs, initiating unexpected higher water permeation. Molecular simulations probe that spongelike or cylindrical aggregates can form to generate transient cluster water pathways through the bilayer. Altogether, the adaptive self-assembly is a key feature influencing channel efficiency. The adaptive channels described here may be considered an important milestone contributing to the systematic discovery of artificial water channels for water desalination.
RESUMO
Self-assembled alkyl-ureido-benzo-15-crown-5-ethers are selective ionophores for K+ cations, which are preferred to Na+ cations. The transport mechanism is determined by the optimal coordination rather than classical dimensional compatibility between the crown ether hole and the cation diameter. Herein, we demonstrate that systematic changes of the structure lead to unexpected modifications in the cation-transport activity and suffice to produce adaptive selection. We show that the main contribution to performance arises from optimal constraints on the conformational freedom, which are determined by the binding macrocycles, the nature of the hydrogen-bonding groups, and the hydrophobic tails. Simple changes to the flexible 15-crown-5-ether lead to selective carriers for Na+ . Hydrophobic stabilization of the channels through mutual interactions between lipids and variable hydrophobic tails appears to be an important cause of increased activity. Oppositely, restricted translocation is achieved when constrained hydrogen-bonded macrocyclic relays are less dynamic in a pore superstructure.
Assuntos
Éteres de Coroa/química , Canais de Potássio/química , Canais de Sódio/química , Sítios de Ligação , Éteres de Coroa/metabolismo , Cristalografia por Raios X , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Transporte de Íons , Ionóforos/química , Ionóforos/metabolismo , Isomerismo , Conformação Molecular , Canais de Potássio/metabolismo , Canais de Sódio/metabolismoRESUMO
Triarylamine molecules appended with crown-ethers or carboxylic moieties form self-assembled supramolecular channels within lipid bilayers. Fluorescence assays and voltage clamp studies reveal that the self-assemblies incorporating the crown ethers work as single channels for the selective transport of K+ or Rb+. The X-ray crystallographic structures confirm the mutual columnar self-assembly of triarylamines and crown-ethers. The dimensional fit of K+ cations within the 18-crown-6 leads to a partial dehydration and to the formation of alternating K+ cation-water wires within the channel. This original type of organization may be regarded as a biomimetic alternative of columnar K+-water wires observed for the natural KcsA channel. Supramolecular columnar arrangement was also shown for the triarylamine-carboxylic acid conjugate. In this latter case, stopped-flow light scattering analysis reveals the transport of water across lipid bilayer membranes with a relative water permeability as high as 17 µm s-1.
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Natural KcsA K(+) channels conduct at high rates with an extraordinary selectivity for K(+) cations, excluding the Na(+) or other cations. Biomimetic artificial channels have been designed in order to mimick the ionic activity of KcSA channels, but simple artificial systems presenting high K(+)/Na(+) selectivity are rare. Here we report an artificial ion channel of H-bonded hexyl-benzoureido-15-crown-5-ether, where K(+) cations are highly preferred to Na(+) cations. The K(+)-channel conductance is interpreted as arising in the formation of oligomeric highly cooperative channels, resulting in the cation-induced membrane polarization and enhanced transport rates without or under pH-active gradient. These channels are selectively responsive to the presence of K(+) cations, even in the presence of a large excess of Na(+). From the conceptual point of view, these channels express a synergistic adaptive behavior: the addition of the K(+) cation drives the selection and the construction of constitutional polarized ion channels toward the selective conduction of the K(+) cation that promotes their generation in the first place.
Assuntos
Potenciais da Membrana , Canais de Potássio/fisiologia , Ligação de HidrogênioRESUMO
The natural KcsA K+ channel, one of the best-characterized biological pore structures, conducts K+ cations at high rates while excluding Na+ cations. The KcsA K+ channel is of primordial inspiration for the design of artificial channels. Important progress in improving conduction activity and K+ /Na+ selectivity has been achieved with artificial ion-channel systems. However, simple artificial systems exhibiting K+ /Na+ selectivity and mimicking the biofunctions of the KcsA K+ channel are unknown. Herein, an artificial ion channel formed by H-bonded stacks of squalyl crown ethers, in which K+ conduction is highly preferred to Na+ conduction, is reported. The K+ -channel behavior is interpreted as arising from discreet stacks of dimers resulting in the formation of oligomeric channels, in which transport of cations occurs through macrocycles mixed with dimeric carriers undergoing dynamic exchange within the bilayer membrane. The present highly K+ -selective macrocyclic channel can be regarded as a biomimetic alternative to the KcsA channel.
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Within biological systems, natural channels and pores transport metabolites across the cell membranes. Researchers have explored artificial ion-channel architectures as potential mimics of natural ionic conduction. All these synthetic systems have produced an impressive collection of alternative artificial ion-channels. Amazingly, researchers have made far less progress in the area of synthetic water channels. The development of synthetic biomimetic water channels and pores could contribute to a better understanding of the natural function of protein channels and could offer new strategies to generate highly selective, advanced water purification systems. Despite the imaginative work by synthetic chemists to produce sophisticated architectures that confine water clusters, most synthetic water channels have used natural proteins channels as the selectivity components, embedded in the diverse arrays of bioassisted artificial systems. These systems combine natural proteins that present high water conductance states under natural conditions with artificial lipidic or polymeric matrixes. Experimental results have demonstrated that natural biomolecules can be used as bioassisted building blocks for the construction of highly selective water transport through artificial membranes. A next step to further the potential of these systems was the design and construction of simpler compounds that maintain the high conduction activity obtained with natural compounds leading to fully synthetic artificial biomimetic systems. Such studies aim to use constitutional selective artificial superstructures for water/proton transport to select functions similar to the natural structures. Moving to simpler water channel systems offers a chance to better understand mechanistic and structural behaviors and to uncover novel interactive water-channels that might parallel those in biomolecular systems. This Account discusses the incipient development of the first artificial water channels systems. We include only systems that integrate synthetic elements in their water selective translocation unit. Therefore, we exclude peptide channels because their sequences derive from the proteins in natural channels. We review many of the natural systems involved in water and related proton transport processes. We describe how these systems can fit within our primary goal of maintaining natural function within bioassisted artificial systems. In the last part of the Account, we present several inspiring breakthroughs from the last decade in the field of biomimetic artificial water channels. Researchers have synthesized and tested hydrophobic, hydrophilic and hybrid nanotubular systems. All these examples demonstrate how the novel interactive water-channels can parallel biomolecular systems. At the same time these simpler artificial water channels offer a means of understanding the molecular-scale hydrodynamics of water for many biological scenarios.
Assuntos
Biomimética , Canais Iônicos , Modelos Biológicos , Proteínas/química , Água/química , Água/metabolismo , Calixarenos , Compostos de Amônio Quaternário/químicaRESUMO
Shatruk and Alabugin propose an alternative structural model for the observed electron density that we have attributed to the photochemical formation of 1,3-dimethylcyclobutadiene in a protective solid crystalline matrix. The main criticism from Shatruk and Alabugin concerns the modeling of the disorder in the calixarene cavity and in particular the neglect of a residual electron density close to the O1 atom. We published (Chem. Eur. J. 2011, 17, 10021) our opinion concerning this "ignored peak" in the Supporting Information of the paper. The current response to the Correspondence demonstrates that Shatruk and Alabugin have over-modeled our data by assigning a small electron density peak, which is hardly more than the density corresponding to a hydrogen atom, to an under-occupied oxygen site, using inappropriate refinement contraints.
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Following earlier reports on the photochemical synthesis of 1,3-dimethylcyclobutadiene in a protective host matrix, theoretical calculations for the formation of that adduct have been recently performed by Rzepa. The author formulated criticisms based mainly on density functional theory calculations of (1)H NMR spectra. According to Rzepa the calculated spectra do not correspond with our measured spectra, which leads him to the conclusion that our interpretation is wrong, and that mainly cyclobutadiene has not been stabilized or even synthesized; we believe, however, that the initial model that Rzepa used for his calculations does not correspond to chemical reality or is at the very least a crude simplification of it, which implies that his calculations cannot match, in every point, our experimental spectra. Rzepa's simplified models might be 'reasonable' from the theoretical point of view; however, in the case of assessment in the solid state, the theoretical setup does not force the system to preserve the confined stabilizing space defined by the crystalline matrix for encapsulated hosts in the solid state. Inversely, in the case of solution modeling, the theoretical setup is too rigid to properly assess the complex equilibria occurring in solution and to accurately determine the NMR spectra of exchanging species in solution. The inconsistency between our experimental results and the results of the theoretical models proposed by Rzepa is such that his conclusions are considered to be too far from experimental reality. Accurate modeling taking in account "reasonable" experimental details would be a worthwhile endeavor.
RESUMO
In the title compound, [Na(2)(N(3))(2)(C(21)H(34)N(2)O(6))(2)]·2CHCl(3), the sodium cation is hepta-coordinated by five O atoms of the crown ether unit of the 1-hexyl-3-(2,3,5,6,8,9,11,12-octa-hydro-1,4,7,10,13-benzopenta-oxacyclo-penta-decin-15-yl)urea (L) ligand, the O atom of the urea group of the second, symmetry-related L ligand, and one N atom of the azide anion. The experimentally determined distance 2.472â (2)â Å between the terminal azide N atom and the sodium cation is substanti-ally longer than that predicted from density functional theory (DFT) calculations (2.263â Å). The crown ethers complexing the sodium cation are related by an inversion centre and form dimers. The urea groups of the two L ligands are connected in a head-to-tail fashion by classical N-Hâ¯N hydrogen-bonding inter-actions and form a ribbon-like structure parallel to the b axis. Parallel ribbons are weakly linked through C-Hâ¯N, C-Hâ¯O and C-Hâ¯π inter-actions.
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INX-08189 is an aryl-phosphoramidate of 6-O-methyl-2'-C-methyl guanosine. INX-08189 was highly potent in replicon assays, with a 50% effective concentration of 10±6 nM against hepatitis C genotype 1b at 72 h. The inhibitory effect on viral replication was rapid, with a 50% effective concentration (EC50) of 35±8 nM at 24 h. An intracellular 2'-C-methyl guanosine triphosphate (2'-C-MeGTP) concentration of 2.43±0.42 pmol/10(6) cells was sufficient to achieve 90% inhibition of viral replication. In vitro resistance studies confirmed that the S282T mutation in the NS5b gene conferred an approximately 10-fold reduction in sensitivity to INX-08189. However, the complete inhibition of S282T mutant replicons still could be achieved with an EC90 of 344±170 nM. Drug combination studies of INX-08189 and ribavirin indicated significant synergy in antiviral potency both in wild-type and S282T-expressing replicons. Genotype 1b replicons could be cleared after 14 days of culture when exposed to as little as 20 nM INX-08189. No evidence of mitochondrial toxicity was observed after 14 days of INX-08189 exposure in both HepG2 and CEM human cell lines. In vivo studies of rats and cynomolgus monkeys demonstrated that 2'-C-MeGTP concentrations in liver equivalent to the EC90 could be attained after a single oral dose of INX-08189. Rat liver 2'-C-MeGTP concentrations were proportional to dose, sustained for greater than 24 h, and correlated with plasma concentrations of the nucleoside metabolite 2'-C-methyl guanosine. The characteristics displayed by INX-08189 support its continued development as a clinical candidate for the treatment of chronic HCV infection.
Assuntos
Amidas/química , Antivirais/farmacologia , Antivirais/farmacocinética , Guanosina/farmacologia , Guanosina/farmacocinética , Hepacivirus/efeitos dos fármacos , Ácidos Fosfóricos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/farmacocinética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Guanosina/análogos & derivados , Guanosina/química , Humanos , Macaca fascicularis , Masculino , Pró-Fármacos/química , Ratos , Ratos Sprague-Dawley , Replicação Viral/efeitos dos fármacosRESUMO
Cyclobutadiene (CBD), the smallest cyclic hydrocarbon bearing conjugated double bonds, has long intrigued chemists because of its chemical characteristics. The question of whether the molecule could be prepared at all has been answered, but the parent compound and its unperturbed derivatives have eluded crystallographic characterization or synthesis "in water". Different approaches have been used to generate and to trap cyclobutadiene in a variety of confined environments: a) an Ar matrix at cryogenic temperatures, b) a hemicarcerand cage enabling the characterization by NMR spectroscopy in solution, and c) a crystalline guanidinium-sulfonate-calixarene G(4)C matrix that is stable enough to allow photoreactions in the solid state. In the latter case, the 4,6-dimethyl-α-pyrone precursor, Me(2)1, has been immobilized in a guanidinium-sulfonate-calixarene G(4)C crystalline network through a combination of non-covalent interactions. UV irradiation of the crystals transforms the entrapped Me(2)1 into a 4,6-dimethyl-Dewar-ß-lactone intermediate, Me(2)2, and rectangular-bent 1,3-dimethylcyclobutadiene, Me(2)CBD(R), which are sufficiently stable under the confined conditions at 175â K to allow a conventional structure determination by X-ray diffraction. Further irradiation drives the reaction towards Me(2)3&Me(2)CBD(S)/CO(2) (63.7 %) and Me(2)CBD(R) (37.3 %) superposed crystalline architectures and the amplification of Me(2)CBD(R). The crystallographic models are supported by additional FTIR and Raman experiments in the solid state and by (1)Hâ NMR spectroscopy and ESI mass spectrometry experiments in aqueous solution. Amazingly, the 4,6-dimethyl-Dewar-ß-lactone, Me(2)2, the cyclobutadiene-carboxyl zwitterion, Me(2)3, and 1,3-dimethylcyclobutadiene, Me(2)CBD, were obtained by ultraviolet irradiation of an aqueous solution of G(4)C{Me(2)1}. 1,3-Dimethylcyclobutadiene is stable in water at room temperature for several weeks and even up to 50 °C as demonstrated by (1)Hâ NMR spectroscopy.
RESUMO
We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2'-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Guanosina Monofosfato/análogos & derivados , Hepacivirus/efeitos dos fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , AMP Desaminase/metabolismo , Amidas/química , Amidas/metabolismo , Antivirais/química , Linhagem Celular Tumoral , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Guanosina Monofosfato/química , Guanosina Monofosfato/farmacologia , Hepacivirus/fisiologia , Hepatite C/tratamento farmacológico , Humanos , Hidrólise , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Nucleosídeos/farmacologia , Ácidos Fosfóricos/química , Ácidos Fosfóricos/metabolismo , Fosforilação , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
We herein report a novel double pro-drug approach applied to the anti-HCV agent 2'-beta-C-methyl guanosine. A phosphoramidate ProTide motif and a 6-O-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Modification of the ester and amino acid moieties lead to a compound INX-08189 that exhibits 10nM potency in the HCV genotype 1b subgenomic replicon, thus being 500 times more potent than the parent nucleoside. The potency of the lead compound INX-08189 was shown to be consistent with intracellular 2'-C-methyl guanosine triphosphate levels in primary human hepatocytes. The separated diastereomers of INX-08189 were shown to have similar activity in the replicon assay and were also shown to be similar substrates for enzyme processing. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV infection.
Assuntos
Antivirais/síntese química , Guanosina Monofosfato/análogos & derivados , Hepacivirus/efeitos dos fármacos , Pró-Fármacos/síntese química , Amidas/química , Antivirais/química , Antivirais/toxicidade , Células Cultivadas , Desenho de Fármacos , Guanosina/análogos & derivados , Guanosina/síntese química , Guanosina/toxicidade , Guanosina Monofosfato/síntese química , Guanosina Monofosfato/química , Guanosina Monofosfato/farmacologia , Humanos , Ácidos Fosfóricos/química , Pró-Fármacos/química , Pró-Fármacos/toxicidadeRESUMO
The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic proteins and provides cancerous proliferating cells with proteins and therefore biomass. Indeed, cancer is associated with an increase in ribosome biogenesis and mutations in several ribosomal proteins genes are found in ribosomopathies, which are congenital diseases that display an elevated risk of cancer. Ribosomes and their biogenesis therefore represent attractive anti-cancer targets and several strategies are being developed to identify efficient and specific drugs. Homoharringtonine (HHT) is the only direct ribosome inhibitor currently used in clinics for cancer treatments, although many classical chemotherapeutic drugs also appear to impact on protein synthesis. Here we review the role of the human ribosome as a medical target in cancer, and how functional and structural analysis combined with chemical synthesis of new inhibitors can synergize. The possible existence of oncoribosomes is also discussed. The emerging idea is that targeting the human ribosome could not only allow the interference with cancer cell addiction towards protein synthesis and possibly induce their death but may also be highly valuable to decrease the levels of oncogenic proteins that display a high turnover rate (MYC, MCL1). Cryo-electron microscopy (cryo-EM) is an advanced method that allows the visualization of human ribosome complexes with factors and bound inhibitors to improve our understanding of their functioning mechanisms mode. Cryo-EM structures could greatly assist the foundation phase of a novel drug-design strategy. One goal would be to identify new specific and active molecules targeting the ribosome in cancer such as derivatives of cycloheximide, a well-known ribosome inhibitor.
Assuntos
Microscopia Crioeletrônica , Desenho de Fármacos , Neoplasias/metabolismo , Ribossomos/metabolismo , Microscopia Crioeletrônica/métodos , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Biossíntese de Proteínas/fisiologia , Ribossomos/química , Ribossomos/genéticaRESUMO
A new synthesis of an oxazoline analogue of apratoxin A has been performed using a solid support. The efficient synthesis of the polyketide part on gram scale and the serine vinylogue is described. The use of chlorotrityl resin allowed the construction of two linear precursors corresponding to two different cyclization sites. This study describes a facile synthesis of analogues for future SAR studies of this potent antitumor compound.
Assuntos
Antineoplásicos/síntese química , Depsipeptídeos/síntese química , Oxazóis/química , Ciclização , Macrolídeos , SerinaRESUMO
Gramicidin A (gA) is the simplest known natural channel, and important progress in improving conduction activity has previously been obtained with modified natural gAs. However, simple artificial systems mimicking the gA functions are unknown. Here we show that gA can be mimicked using a simple synthetic triazole or 'T-channel' forming compound (TCT), having similar constitutional functions as the natural gAs. As in gA channels, the carbonyl moieties of the TCT, which point toward the T-channel core and surround the transport direction, are solvated by water. The net-dipolar alignment of water molecules along the chiral pore surfaces influences the conduction of protons/ions, envisioned to diffuse along dipolar hydrophilic pathways. Theoretical simulations and experimental assays reveal that the conduction through the T-channel, similar to that in gA, presents proton/water conduction, cation/anion selectivity and large open channel-conductance states. T-channels--associating supramolecular chirality with dipolar water alignment--represent an artificial primitive mimic of gA.
Assuntos
Gramicidina , Íons/metabolismo , Bicamadas Lipídicas/metabolismo , Proteínas de Membrana Transportadoras , Água/metabolismo , Potenciais da Membrana , Técnicas de Patch-Clamp , Triazóis/metabolismoRESUMO
Constitutional mesoporous thin-layer electrodes have been used to generate confined fullerene wires allowing a capacitive diffusion of electrons.
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Multivalent biorecognition of lectin layers by glyconanoparticle sugar-clusters has been used to generate multilayer nanoplatform architectures in a QCM sensing setup.