Development of anti-inflammatory peptidomimetics based on the structure of human alpha1-antitrypsin

Human α1-antitrypsin (hAAT) has two distinguishing functions: anti-protease activity and regulation of the immune system. In the present study we hypothesized that those two protein functions are mediated by different structural domains on the hAAT surface. Indeed, such biologically active immunoregulatory sites (not associated with canonical anti-protease activity) on the surface of hAAT were identified by in silico methods. Several peptides were derived from those immunoregulatory sites. Four peptides exhibited impressive biological effects in pharmacological concentration ranges. Peptidomimetic (14) was developed, based on the structure of the most druggable and active peptide. The compound exhibited a potent anti-inflammatory activity in vitro and in vivo. Such a compound could be used as a basis for developing novel anti-inflammatory drug candidates and as a research tool for better understanding hAAT functions. [Display omitted] •The immunomodulatory effects of human alpha1-antitrypsin (hAAT) were studied.•The binding pockets were identified, using molecular modeling putative hAAT.•Several peptides derived from hAAT binding pockets exhibited immunomodulatory effects.•Several peptidomimetics were developed, based on the structures of active peptides.•One of them (compound 14) exhibited a significant biological effect in vivo.