RESUMO
Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased ß-amyloid (Aß) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Receptores de Superfície Celular/agonistas , Receptores de Superfície Celular/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , LigantesRESUMO
Herein we introduce the derivation of a mathematical expression to evaluate the dissociation constant of a mixture of stereoisomers in equal amounts (KdMIX), when the corresponding dissociation constants (Kd) or medium response (MR50) of the pure stereoisomers are known; the final equation takes the form of the harmonic mean. In order to validate the equation, we carried out a bibliographic search of experimental data of enantiomeric molecules with biological activity, considering the Kd's or MR50's of the isolated enantiomers as well as that of the racemate. The comparisons between the experimental dissociation constants of the mixtures (KdEXP or MR50EXP) and the calculated values (KdMIX or MR50MIX) were consistent; the similarity between these values is supported through statistical analyses of group comparison and simple linear correlation. The equation we obtained, which corresponds to the harmonic mean, was used to predict the values of KdMIX (or MR50MIX) or Kd (or MR50) in systems when only two of the experimental values are known: either the dissociation constants of both enantiomers or the Kd (or MR50) of one of the enantiomers and dissociation constant of the racemate.
Assuntos
Produtos Biológicos/química , Células Eucarióticas/efeitos dos fármacos , Modelos Estatísticos , Receptores de Superfície Celular/metabolismo , Animais , Produtos Biológicos/farmacologia , Células Eucarióticas/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Receptores de Superfície Celular/agonistas , Receptores de Superfície Celular/antagonistas & inibidores , EstereoisomerismoRESUMO
Imiquimod, an immune response modifier with potent antiviral and antitumor properties, has been reported to be effective in the treatment of various cutaneous neoplasms. Besides stimulating the production of pro-inflammatory cytokines through Toll-like receptors on the surface of dendritic cells of monocyte-macrophage lineage, novel antiapoptotic mechanisms have been identified.
Assuntos
Adjuvantes Imunológicos/farmacologia , Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Administração Cutânea , Aminoquinolinas/administração & dosagem , Aminoquinolinas/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Humanos , Imiquimode , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/metabolismo , Receptores de Superfície Celular/agonistas , Receptores de Superfície Celular/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Receptores Toll-LikeRESUMO
Pretreatment of macrophages with Toll-like receptor (TLR)2 or TLR4 agonists leads to a stage of cell hyporesponsiveness to a second stimulation with TLR agonists. This tolerance state is accompanied by the repression of IL-1 receptor-associated kinase-1, mitogen-activated protein kinases, and IkappaB phosphorylation and expression of genes encoding proinflammatory cytokines, like IL-1beta and TNF-alpha. In this report, we demonstrated that mucin-like glycoprotein (tGPI-mucin) of Trypanosoma cruzi trypomastigotes (TLR2 agonist) and LPS (TLR4 agonist) induce cross-tolerance in macrophages and we addressed the role of phosphatase activity in this process. Analysis of the kinetic of phosphatase activity induced by tGPI-mucin or LPS revealed maximum levels between 12 and 24 h, which correlate with the macrophage hyporesponsiveness stage. The addition of okadaic acid, an inhibitor of phosphatase activity, reversed macrophage hyporesponsiveness after exposure to either LPS or tGPI-mucin, allowing phosphorylation of IL-1R-associated kinase-1, mitogen-activated protein kinases, and IkappaB and leading to TNF-alpha gene transcription and cytokine production. Furthermore, pretreatment with either the specific p38/stress-activated protein kinase-2 inhibitor (SB203580) or the NF-kappaB translocation inhibitor (SN50) prevented the induction of phosphatase activity and hyporesponsiveness in macrophage, permitting cytokine production after restimulation with LPS. These results indicate a critical role of p38/stress-activated protein kinase-2 and NF-kappaB-dependent phosphatase in macrophage hyporesponsiveness induced by microbial products that activate TLR2 and TLR4.