Abstract

Cystic Fibrosis (CF) is the most common lethal autosomal recessive disorder in Caucasia population, affecting approximately 30,000 people in the United States and ∼70,000 worldwide. While there is yet no cure for CF, aggressive treatment including mucus thinners, antibiotics, anti-inflammatories and bronchodilators along with physical therapy and proper nutritional repletion, can lengthen and improve the quality of life of CF patients. Peptides derived from mutant CFTR protein which inhibit intracellular degradation and/or retention of mutant CFTR proteins have been clinially used. Methods of inhibiting intracellular degradation and/or retention of mutant CFTR protein by administering peptides having an amino acid sequence corresponding to mutant CFTR amino acid sequences have also been reported in other studies. Further, methods of preventing cellular retention and degradation of an otherwise membrane bound protein by competitively inhibiting intracellular degradation (proteolysis) and retention which would otherwise retain or degrade synthesized mutant proteins prior to arrival of the protein at the cell surface have previously been tested. In our project we conducted a fragment-ligand based structure drug discovery procedure through a ligand-based high throughput screening of 150,000 chemically diverse compounds and of more than 1,500 analogs of active compounds yielded several classes of CFTR corrector multi-targeted to the conserved cystic fibrosis over-expressed nucleic acid binding sites mutant domains. Previous biochemical studies also suggested a mechanism of action involving improved CFTR folding at the ER increased stability at the cell surface. Previous reffered biologically active peptides have been used to inhibit intracellular degradation (proteolysis) and/or retention processes to treat or cure Cystic Fibrosis disease. Peptides are short-lived and typically involve short amino acid stretches bearing few “hot spots”, thus the identification of molecules able to mimic them may produce important lead compounds for the treatment of CF. Here, we have for the first time discovered Small Asn-Ile-Ile-Gly-Val-Ser-Tyr peptide-mimetic of high free energy binding site CFTR similar analog molecules for the correction of Cystic Fibrosis pathological genes discovered by using the BiogenetoligandorolTM, a new cluster of algorithms structure-based virtual screening molecular tools.