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1.
J Mater Chem B ; 12(8): 1991-2005, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38333942

RESUMO

Protein misfolding and its aggregation, known as amyloid aggregates (Aß), are some of the major causes of more than 20 diseases such as Parkinson's disease, Alzheimer's disease, and type 2 diabetes. The process of Aß formation involves an energy-driven oligomerization of Aß monomers, leading to polymerization and eventual aggregation into fibrils. Aß fibrils exhibit multilevel chirality arising from its amino acid residues and the arrangement of folded polypeptide chains; thus, a chirality-driven approach can be utilized for the detection and inhibition of Aß fibrils. In this regard, chiral nanomaterials have recently opened new possibilities for various biomedical applications owing to their stereoselective interaction with biological systems. Leveraging this chirality-driven approach with chiral nanomaterials against protein-aggregated diseases could yield promising results, particularly in the early detection of Aß forms and the inhibition of Aß aggregate formation via specific and strong "chiral-chiral interaction." Despite the advantages, the development of advanced theranostic systems using chiral nanomaterials against protein-aggregated diseases has received limited attention so far because of considerably limited formulations for chiral nanomaterials and lack of information of their chiroptical behavior. This review aims to present the current status of chiral nanomaterials explored for detecting and inhibiting Aß forms. This review covers the origin of chirality in amyloid fibrils and nanomaterials and different chiral detection methods; furthermore, different chiral nanosystems such as chiral plasmonic nanomaterials, chiral carbon-based nanomaterials, and chiral nanosurfaces, which have been used so far for different therapeutic applications against protein-aggregated diseases, are discussed in detail. The findings from this review may pave the way for the development of novel approaches using chiral nanomaterials to combat diseases resulting from protein misfolding and can further be extended to other disease forms.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Nanoestruturas , Humanos , Peptídeos beta-Amiloides/metabolismo , Agregados Proteicos , Doença de Alzheimer/tratamento farmacológico , Amiloide/química , Nanoestruturas/uso terapêutico
2.
J Nat Prod ; 86(5): 1222-1229, 2023 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-37099442

RESUMO

Cyclotides are a unique family of stable and cyclic mini-proteins found in plants that have nematicidal and anthelmintic activities. They are distributed across the Rubiaceae, Violaceae, Fabaceae, Cucurbitaceae, and Solanaceae plant families, where they are posited to act as protective agents against pests. In this study, we tested the nematicidal properties of extracts from four major cyclotide-producing plants, Oldenlandia affinis, Clitoria ternatea, Viola odorata, and Hybanthus enneaspermus, against the free-living model nematode Caenorhabditis elegans. We evaluated the nematicidal activity of the cyclotides kalata B1, cycloviolacin O2, and hyen D present in these extracts and found them to be active against the larvae of C. elegans. Both the plant extracts and isolated cyclotides exerted dose-dependent toxicity on the first-stage larvae of C. elegans. Isolated cyclotides caused death or damage upon interacting with the worms' mouth, pharynx, and midgut or membrane. Cycloviolacin O2 and hyen D produced bubble-like structures around the C. elegans membrane, termed blebs, implicating membrane disruption causing toxicity and death. All tested cyclotides lost their toxicity when the hydrophobic patches present on them were disrupted via a single-point mutation. The present results provide a facile assay design to measure and explore the nematicidal activities of plant extracts and purified cyclotides on C. elegans.


Assuntos
Ciclotídeos , Fabaceae , Nematoides , Violaceae , Animais , Antinematódeos/farmacologia , Caenorhabditis elegans , Ciclotídeos/farmacologia , Ciclotídeos/química , Fabaceae/química , Extratos Vegetais/química , Proteínas de Plantas/química
3.
J Nat Prod ; 83(12): 3736-3743, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33296204

RESUMO

Hybanthus enneaspermus is an Indian folk medicinal herb that has been widely used as a libido enhancer. This plant belongs to the Violaceae plant family, which ubiquitously contains disulfide-rich cyclic peptides named cyclotides. Cyclotides are an expanding plant-derived peptide family with numerous interesting bioactivities, and their unusual stability against proteolysis has attracted much attention in drug design applications. Recently, H. enneaspermus has been reported to be a rich source of cyclotides, and hence, it was of interest to investigate whether cyclotides contribute to its aphrodisiac activity. In this study, we evaluated the in vivo aphrodisiac activity of the herbal powder, extract, and the most abundant cyclotide, hyen D, extracted from H. enneaspermus on rats in a single dose regimen. After dosing, the sexual behaviors of male rats were observed, recorded, analyzed, and compared with those of the vehicle group. The results show that the extract and hyen D significantly decreased the intromission latency of sexually naïve male rats and the extract improved a range of other measured sexual parameters. The results suggest that the extract could enhance libido as well as facilitate erectile function in male rats and that the cyclotide hyen D could contribute to the libido-enhancing activity of this ethnomedicinal herb.


Assuntos
Afrodisíacos/farmacologia , Extratos Vegetais/farmacologia , Violaceae/química , Animais , Feminino , Masculino , Ratos , Comportamento Sexual Animal
4.
Artigo em Inglês | MEDLINE | ID: mdl-25965519

RESUMO

Amylamine constitutes an important class of organic compounds which exists in a variety of ammonia derivatives. In present study, a comparative analysis of amylamine and its two potential isomers, iso-amylamine and tert-amylamine, has been performed using density functional theory with B3LYP method and 6-311G(d,p) as the basis set. The equilibrium structures of amylamine as well as its iso and tert forms have been obtained. The vibrational spectroscopic analysis has been carried out for the three molecules and complete assignments to all possible modes have been offered. The HOMO, LUMO and MESP surfaces are analyzed to discuss the chemical reactivity patterns in the molecules. A number of reactivity parameters have been calculated to further explain their chemical reactivity. The thermodynamic and nonlinear optical parameters are also calculated and discussed.


Assuntos
Aminas/química , Isomerismo , Modelos Moleculares , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman
5.
J Pharmacol Exp Ther ; 334(1): 244-54, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20354177

RESUMO

The role of neuropeptide FF (NPFF) and its analogs in pain modulation is ambiguous. Although NPFF was first characterized as an antiopioid peptide, both antinociceptive and pronociceptive effects have been reported, depending on the route of administration. Currently, two NPFF receptors, termed FF1 and FF2, have been identified and cloned, but their roles in pain modulation remain elusive because of the lack of availability of selective compounds suitable for systemic administration in in vivo models. Ligand-binding studies confirm ubiquitous expression of both subtypes in brain, whereas only FF2 receptors are expressed spinally. This disparity in localization has served as the foundation of the hypothesis that FF1 receptors mediate the pronociceptive actions of NPFF. We have identified novel small molecule NPFF receptor agonists and antagonists with varying degrees of FF2/FF1 functional selectivity. Using these pharmacological tools in vivo has allowed us to define the roles of NPFF receptor subtypes as pertains to the modulation of nociception. We demonstrate that selective FF2 agonism does not modulate acute pain but instead ameliorates inflammatory and neuropathic pains. Treatment with a nonselective FF1/FF2 agonist potentiates allodynia in neuropathic rats and increases sensitivity to noxious thermal and to non-noxious mechanical stimuli in normal rats in an FF1 antagonist-reversible manner. Treatment with FF1 antagonists reversed established mechanical allodynia, indicating the possibility of increased NPFF tone through FF1 receptors. In conclusion, we provide evidence for the opposing roles of NPFF receptors and highlight selective FF2 agonism and/or selective FF1 antagonism as potential targets warranting further investigation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Oligopeptídeos/metabolismo , Receptores de Neuropeptídeos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , AMP Cíclico/antagonistas & inibidores , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Ligantes , Masculino , Camundongos , Mononeuropatias/tratamento farmacológico , Mononeuropatias/metabolismo , Células NIH 3T3 , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Ratos , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/genética , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Transfecção
6.
Neuropharmacology ; 58(2): 365-73, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19835892

RESUMO

The recent discovery of allosteric potentiators and agonists of the muscarinic M(1) receptor represents a significant advance in the muscarinic receptor pharmacology. In the current study we describe the receptor pharmacology and pro-cognitive action of the allosteric agonist AC-260584. Using in vitro cell-based assays with cell proliferation, phosphatidylinositol hydrolysis or calcium mobilization as endpoints, AC-260584 was found to be a potent (pEC(50) 7.6-7.7) and efficacious (90-98% of carbachol) muscarinic M(1) receptor agonist. Furthermore, as compared to orthosteric binding agonists, AC-260584 showed functional selectivity for the M(1) receptor over the M(2), M(3), M(4) and M(5) muscarinic receptor subtypes. Using GTPgammaS binding assays, its selectivity was found to be similar in native tissues expressing mAChRs to its profile in recombinant systems. In rodents, AC-260584 activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in the hippocampus, prefrontal cortex and perirhinal cortex. The ERK1/2 activation was dependent upon muscarinic M(1) receptor activation since it was not observed in M(1) knockout mice. AC-260584 also improved the cognitive performance of mice in the novel object recognition assay and its action is blocked by the muscarinic receptor antagonist pirenzepine. Taken together these results indicate for the first time that a M(1) receptor agonist selective over the other mAChR subtypes can have a symptomatically pro-cognitive action. In addition, AC-260584 was found to be orally bioavailable in rodents. Therefore, AC-260584 may serve as a lead compound in the development of M(1) selective drugs for the treatment of cognitive impairment associated with schizophrenia and Alzheimer's disease.


Assuntos
Benzoxazinas/farmacologia , Cognição/efeitos dos fármacos , Nootrópicos/farmacologia , Receptor Muscarínico M1/agonistas , Administração Oral , Animais , Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cognição/fisiologia , Cricetinae , Cricetulus , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Agonistas Muscarínicos/administração & dosagem , Agonistas Muscarínicos/farmacocinética , Agonistas Muscarínicos/farmacologia , Células NIH 3T3 , Nootrópicos/administração & dosagem , Nootrópicos/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M1/genética , Receptor Muscarínico M1/metabolismo , Receptores Muscarínicos/genética , Receptores Muscarínicos/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
7.
Mol Pharmacol ; 70(6): 1974-83, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16959945

RESUMO

Transmembrane domain 3 (TM3) plays a crucial role mediating muscarinic acetylcholine receptor activation by acetylcholine, carbachol, and other muscarinic agonists. We compared the effects of point mutations throughout TM3 on the interactions of carbachol, 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl] piperidine hydrogen chloride (AC-42), a potent structural analog of AC-42 called 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC-260584), N-desmethylclozapine, and clozapine with the M(1) muscarinic receptor. The binding and activation profiles of these ligands fell into three distinct patterns; one exemplified by orthosteric compounds like carbachol, another by structural analogs of AC-42, and a third by structural analogs of N-desmethylclozapine. All mutations tested severely reduced carbachol binding and activation of M(1). In contrast, the agonist actions of AC-42 and AC-260584 were greatly potentiated by the W101A mutation, slightly reduced by Y106A, and slightly increased by S109A. Clozapine and N-desmethylclozapine displayed substantially increased maximum responses at the Y106A and W101A mutants, slightly lower activity at S109A, but no substantial changes in potency. At L102A and N110A, agonist responses to AC-42, AC-260584, clozapine, and N-desmethylclozapine were all substantially reduced, but usually less than carbachol. D105A showed no functional responses to all ligands. Displacement and dissociation rate experiments demonstrated clear allosteric properties of AC-42 and AC-260584 but not for N-desmethylclozapine and clozapine, indicating that they may contact different residues than carbachol to activate M(1) but occupy substantially overlapping spaces, in contrast to AC-42 and AC-260584, which occupy separable spaces. These results show that M(1) receptors can be activated in at least three distinct ways and that there is no requirement for potent muscarinic agonists to mimic acetylcholine interactions with TM3.


Assuntos
Benzoxazinas/farmacologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Agonistas Muscarínicos/farmacologia , Piperidinas/farmacologia , Receptor Muscarínico M1/agonistas , Linhagem Celular , Humanos , Conformação Proteica , Ensaio Radioligante , Receptor Muscarínico M1/química
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