RESUMO
Specific interference with molecular mechanisms guiding tissue localization of leukocytes may be of great utility for selective immunosuppressive therapies. We have discovered and characterized efomycines, a new family of selective small-molecule inhibitors of selectin functions. Members of this family significantly inhibited leukocyte adhesion in vitro. Efomycine M, which was nontoxic and showed the most selective inhibitory effects on selectin-mediated leukocyte-endothelial adhesion in vitro, significantly diminished rolling in mouse ear venules in vivo as seen by intravital microscopy. In addition, efomycine M alleviated cutaneous inflammation in two complementary mouse models of psoriasis, one of the most common chronic inflammatory skin disorders. Molecular modeling demonstrated a spatial conformation of efomycines mimicking naturally occurring selectin ligands. Efomycine M might be efficacious in the treatment of human inflammatory disorders through a similar mechanism.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Selectina E/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Macrolídeos/farmacologia , Psoríase/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Técnicas In Vitro , Macrolídeos/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Modelos Moleculares , Oligossacarídeos/química , Psoríase/patologia , Antígeno Sialil Lewis X , Transplante de Pele , Streptomyces/química , Transplante HeterólogoRESUMO
Neuropeptides control essential physiological processes in insects such as water balance and muscle activity. Due to their metabolic instability and adverse physiochemical properties, insect neuropeptides are unsuited for a direct application in plant protection. As a first approximation towards the biologically active conformation, the structures of selected neuropeptides from economically important pest insects were determined by NMR spectroscopy and fluorescence measurements in a membrane-mimicking environment. A receptor binding model is suggested for the helicokinins and discussed in connection with biological activities and membrane-bound conformations of linear and cyclic analogues.
Assuntos
Proteínas de Insetos/química , Micelas , Peptídeos/química , Animais , Ressonância Magnética Nuclear Biomolecular , Espectrometria de FluorescênciaRESUMO
Starting from natural product podophyllotoxin 1 substituted heterolignans were identified with promising insecticidal in vivo activity. The impact of substitution in each segment of the core structure was investigated in a detailed SAR study, and variation of substituents in both aromatic moieties afforded derivatives 5 and 43 with broad insecticidal activity against lepidopteran and coleopteran species. In vitro measurements supported by modeling studies indicate that heterolignans 3-134 act as tubuline polymerization inhibitors interacting with the colchicine-binding site. Insect specific structure-activity effects were observed showing that the insecticidal SAR described herein differs from reported cytotoxicity studies.
Assuntos
Inseticidas/química , Lignanas/química , Podofilotoxina/química , Moduladores de Tubulina/química , Animais , Besouros/efeitos dos fármacos , Simulação por Computador , Cristalografia por Raios X , Inseticidas/síntese química , Inseticidas/toxicidade , Lepidópteros/efeitos dos fármacos , Lignanas/síntese química , Lignanas/toxicidade , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/toxicidadeRESUMO
Neuropeptides control numerous physiological processes in insects. The regulation of water balance is a crucial aspect of homeostasis in terrestrial insects and has been shown to be under endocrine control, primarily by corticotrophin releasing factor (CRF)-related peptides and kinins. For helicokinin I, a diuretic neuropeptide from the economically important insect pest Heliothis virescens, detailed structure-activity relationships have been established based on truncated structures, diverse amino acid scans and peptidomimetic analogues. The activities of selected compounds on functional expressed helicokinin receptors are compared with the results of a Malphigian tubule assay. Implications for further peptidomimetic variations are provided.
Assuntos
Insetos/metabolismo , Neuropeptídeos/química , Neuropeptídeos/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Ligação Proteica , Receptores de Neuropeptídeos/metabolismo , Relação Estrutura-AtividadeRESUMO
In insects numerous physiological processes are regulated by neuropeptides. Two fluorescent analogues of the amino acids tryptophan and tyrosine were synthesized and incorporated in the diuretic neuropeptide helicokinin I from the moth Heliothis zea. By fluorescence emission measurements it was shown that both fluorescent helicokinin I analogues react sensitive on the dielectricity of their microenvironment. A helicokinin I analogue containing the fluorescent tryptophan mimic beta-[6'-(N,N-dimethyl)-amino-2'-naphthoyl]alanine (Ald) was shown to bind to dodecylphosphocholine (DPC) micelles by the Ald residue. A membrane binding model for helicokinin I is proposed based on data from related mammalian and insect-neuropeptides.