RESUMEN
A first-in-class series of low molecular weight trisubstituted triazines were synthesized and evaluated for their ability to mimic protein A binding to human IgG antibody. The structure-activity relationship (SAR) demonstrates that the 1,3-phenylenediamine component was essential for robust activity. Twenty-two compounds, represented by lead molecule 34, displayed significant activity compared to protein A. These compounds may prove useful for the treatment of autoimmune disease.
Asunto(s)
Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/farmacología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Proteína Estafilocócica A/metabolismo , Triazinas/síntesis química , Triazinas/farmacología , Animales , Anticuerpos Antinucleares/inmunología , Anticuerpos Antinucleares/metabolismo , Materiales Biomiméticos/química , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Riñón/efectos de los fármacos , Riñón/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Ratones , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Proteína Estafilocócica A/inmunología , Relación Estructura-Actividad , Triazinas/químicaRESUMEN
In addition to the already known differences between adenosine deaminase (ADA) and cytidine deaminase (CDA) in terms of their tertiary structure, the sphere of Zn(+2) coordination, and their reverse stereochemical preference, we present evidence that the enzymes also differ significantly in terms of the North/South conformational preferences for their substrates and the extent to which the lack of the O(4') oxygen affects the kinetics of the enzymatic deamination of carbocyclic substrates. The carbocyclic nucleoside substrates used in this study have either a flexible cyclopentane ring or a rigid bicyclo[3.1.0]hexane scaffold.