RESUMEN
Secretory phospholipase A2 (sPLA2) and matrix metallopreoteinases (MMPs) are key enzymes involved in rheumatoid arthritis (RA), and their modulation thus represents a potential therapeutic option. On the basis of Escherichia coli radioassay, synthetic peptides were designed and screened for sPLA2 inhibition. The linear peptide, 10f (PIP-18), inhibited the recombinant human synovial sPLA2 activity with an IC50 of 1.19 microM. Not only did the peptide interfere with the function of sPLA2, but it also appeared to inhibit mRNA expression of sPLA2 and various MMPs in IL-1beta-stimulated RA synovial fibroblast (RASF) cultures and thereby the production of the corresponding proteins (>80% inhibition). Nuclear magnetic resonance (NMR), modeling, and docking studies indicate that in solution the peptide exhibits a beta-turn at residues Trp-Asp-Gly-Val and possibly binds to the hydrophobic channel of sPLA2. The results strongly suggest that the modulatory action of peptide 10f may play a major role in counteracting the development of RA.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Modelos Moleculares , Péptidos/síntesis química , Fosfolipasas A2 Secretoras/antagonistas & inhibidores , Fosfolipasas A2 Secretoras/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Artritis Reumatoide/enzimología , Células Cultivadas , Dicroismo Circular , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Expresión Génica/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Metaloproteinasas de la Matriz/biosíntesis , Oligopéptidos/síntesis química , Oligopéptidos/química , Oligopéptidos/farmacología , Péptidos/química , Péptidos/farmacología , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Fosfolipasas A2 Secretoras/biosíntesis , Unión Proteica , Conformación Proteica , Conejos , Soluciones , Relación Estructura-Actividad , Líquido Sinovial/citologíaRESUMEN
Adhesion molecules participate in many stages of immune response; they regulate leukocyte circulation, lymphoid cell homing to tissues and inflammatory sites, migration across endothelial cells and T-cell stimulation. During T-cell immune response, adhesion molecules form a specialized junction between T-cell and the antigen presenting cell. Thus, many researchers have focused their attention on targeting adhesion molecules for developing therapeutic agents. Most of these efforts are intended to develop drugs for autoimmune and inflammatory diseases. Therapeutic agents like efalizumab and alefacept have been approved by the FDA for the treatment of inflammatory autoimmune diseases. This review focuses on some of the basic aspects and importance of adhesion molecules, recent understanding of the structure of adhesion molecules, and the targeted therapeutic agents.
Asunto(s)
Moléculas de Adhesión Celular , Sistemas de Liberación de Medicamentos/métodos , Diseño de Fármacos , Linfocitos T , Secuencia de Aminoácidos , Animales , Moléculas de Adhesión Celular/química , Moléculas de Adhesión Celular/genética , Humanos , Datos de Secuencia Molecular , Estructura Secundaria de Proteína/fisiología , Linfocitos T/inmunologíaRESUMEN
Neuropeptide Y (NPY), receptors belong to the G-protein coupled receptor superfamily. NPY mediates several physiological responses, such as blood pressure, food intake, sedation. These actions of NPY are mediated by six receptor subtypes denoted as Y1-Y5 and y6. Modeling of receptor subtypes and binding site identification is an important step in developing new therapeutic agents. We have attempted to model the three NPY receptor types, Y1, Y4, and Y5 using homology modeling and threading methods. The models are consistent with previously reported experimental evidence. To understand the interaction and selectivity of NPY analogues with different neuropeptide receptors, docking studies of two neuropeptide analogues (BVD10 and BVD15) with receptors Y1 and Y4 were carried out. Results of the docking studies indicated that the interaction of ligands BVD10 and BVD15 with Y1 and Y4 receptors are different. These results were evaluated for selectivity of peptide analogues BVD10 and BVD15 towards the receptors.
Asunto(s)
Modelos Moleculares , Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/metabolismo , Secuencia de Aminoácidos , Humanos , Ligandos , Modelos Químicos , Datos de Secuencia Molecular , Unión Proteica , Conformación Proteica , Receptores de Neuropéptido Y/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Abstract Neuropeptide Y (NPY), receptors belong to the G-protein coupled receptor superfamily. NPY mediates several physiological responses, such as blood pressure, food intake, sedation. These actions of NPY are mediated by six receptor subtypes denoted as Y(1)-Y(5) and y(6). Modeling of receptor subtypes and binding site identification is an important step in developing new therapeutic agents. We have attempted to model the three NPY receptor types, Y1, Y4, and Y5 using homology modeling and threading methods. The models are consistent with previously reported experimental evidence. To understand the interaction and selectivity of NPY analogues with different neuropeptide receptors, docking studies of two neuropeptide analogues (BVD10 and BVD15) with receptors Y1 and Y4 were carried out. Results of the docking studies indicated that the interaction of ligands BVD10 and BVD15 with Y1 and Y4 receptors are different. These results were evaluated for selectivity of peptide analogues BVD10 and BVD15 towards the receptors.
