RESUMEN
The phospholipase A(2) (PLA(2)) superfamily consists of different groups of enzymes which are characterized by their ability to catalyze the hydrolysis of the sn-2 ester bond in a variety of phospholipid molecules. The products of PLA(2s) activity play divergent roles in a variety of physiological processes. There are four main types of PLA(2s): the secreted PLA(2s) (sPLA(2s)), the cytosolic PLA(2s) (cPLA(2s)), the calcium-independent PLA(2s) (iPLA(2)) and the lipoprotein-associated PLA(2s) (LpPLA(2s)). Various potent and selective PLA2 inhibitors have been reported up to date and have provided outstanding support in understanding the mechanism of action and elucidating the function of these enzymes. The current review focuses on the implementation of rational design through computer-aided drug design (CADD) on the discovery and development of new PLA(2) inhibitors.
Asunto(s)
Diseño Asistido por Computadora , Inhibidores Enzimáticos/química , Inhibidores de Fosfolipasa A2 , Venenos de Abeja/enzimología , Compuestos de Bencidrilo/química , Dominio Catalítico , Cromanos/química , Dicetopiperazinas/química , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Fosfolipasas A2 Grupo II/antagonistas & inhibidores , Humanos , Indoles/química , Modelos Moleculares , Conformación Molecular , Fenoles/química , Fosfolipasas A2/metabolismo , Relación Estructura-Actividad Cuantitativa , Sesquiterpenos/química , Sulfonamidas/farmacología , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/químicaRESUMEN
[Arg(91), Ala(96)] MBP(87-99) is an altered peptide ligand (APL) of myelin basic protein (MBP), shown to actively inhibit experimental autoimmune encephalomyelitis (EAE), which is studied as a model of multiple sclerosis (MS). The APL has been rationally designed by substituting two of the critical residues for recognition by the T-cell receptor. A conformational analysis of the APL has been sought using a combination of 2D NOESY nuclear magnetic resonance (NMR) experiments and detailed molecular dynamics (MD) calculations, in order to comprehend the stereoelectronic requirements for antagonistic activity, and to propose a putative bioactive conformation based on spatial proximities of the native peptide in the crystal structure. The proposed structure presents backbone similarity with the native peptide especially at the N-terminus, which is important for major histocompatibility complex (MHC) binding. Primary (Val(87), Phe(90)) and secondary (Asn(92), Ile(93), Thr(95)) MHC anchors occupy the same region in space, whereas T-cell receptor (TCR) contacts (His(88), Phe(89)) have different orientation between the two structures. A possible explanation, thus, of the antagonistic activity of the APL is that it binds to MHC, preventing the binding of myelin epitopes, but it fails to activate the TCR and hence to trigger the immunologic response. NMR experiments coupled with theoretical calculations are found to be in agreement with X-ray crystallography data and open an avenue for the design and synthesis of novel peptide restricted analogues as well as peptide mimetics that rises as an ultimate goal.
Asunto(s)
Modelos Moleculares , Proteína Básica de Mielina/química , Fragmentos de Péptidos/química , Secuencia de Aminoácidos , Aminoácidos Aromáticos/química , Animales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Humanos , Ligandos , Datos de Secuencia Molecular , Proteína Básica de Mielina/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Conformación ProteicaRESUMEN
Confronting Multiple Sclerosis requires as an underlying step the manipulation of immune response through modification of Myelin Basic Protein peptides. The aim is to design peptidic or nonpeptidic molecules that compete for recognition of self-antigens at the level of antigen presentation. The rational approach is to substitute residues that serve as anchors for the T-Cell Receptor with others that show no binding at all, and those that serve as Major Histocompatibility Complex II anchors with others that present increased binding affinity. The resulting structure, hence, retains normal or increased MHC II binding properties, but fails to activate disease-inducing T-cells. This rational design can only be achieved by identifying the structural requirements for binding of the natural peptide to MHC II, and the anchor residues with their corresponding specific pockets in the binding groove. The peptide-MHC II complex then interacts with the TCR; thus, an additional way to trigger the desired immune response is to alter secondary anchor residues as well as primary ones. In this review, the structural requirements for binding of MBP peptides to MHC II are presented, as are the mechanism and key features for TCR recognition of the peptide-MHC II complex.