Synthetic inducible biological response amplifiers (SIBRAs): rational peptides at the crossroads between molecular evolution and structure-based drug design.
The present study proposes a novel type of synthetic chimaeric polypeptides potentially useful in the therapy of various diseases. The prototype peptide termed 'synthetic inducible biological response amplifier' (SIBRA) would comprise a ligand-binding site, a DNA-binding region, a trans-activating domain as well as strings of residues ensuring bioavailability and targeting to specific compartments such as the cell nucleus. These domains would be selected from cellular proteins, artificially tailored to a SIBRA and further modified towards a molecule with both in vivo and intracellular activity. Since proposed to resemble a host molecule with autoregulatory properties, a SIBRA would be activated upon exposure to a defined environmental stimulus and amplify host responses appropriate for this stimulus. Proteins would accumulate that share functional domains with the administered SIBRA and have a positive autoregulatory capacity. The latter may involve the interaction of the induced protein with the promoter of its gene resulting in a direct positive autoregulatory loop or require the induction of intermediary proteins that eventually upregulate the production of SIBRA-like host proteins. Since the ligand-binding site of a SIBRA is rationally designed to target a pathogenic protein, SIBRAs could be regarded as the product of an artificial acceleration and refinement of strategies intrinsic to the immune system.
Radulescu
R T
RT
Molecular Concepts Research (MCR), Munich, Germany.
D001682:Biological Availability; D004268:DNA-Binding Proteins; D015195:Drug Design; D004358:Drug Therapy / Q000379:methods; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis*; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis*; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D007155:Immunologic Factors; D008024:Ligands; D010455:Peptides; D011993:Recombinant Fusion Proteins