Issue Date: April 30, 2012
Computer Design Leads To Cystic Fibrosis Drug Candidates
Starting with the structure of a protein related to cystic fibrosis, Duke University computational chemists have gone from theory to possible drug candidates for the disease (PLoS Comput. Biol., DOI: 10.1371/journal.pcbi.1002477). Cystic fibrosis is an inherited condition in which mucus builds up in the lungs and digestive tract, making it difficult to breathe and absorb food nutrients. The underlying cause is a defective gene that encodes a mutated version of the protein CFTR (cystic fibrosis transmembrane conductance regulator). The mutated protein misfolds, has impaired functionality, and is degraded abnormally fast; all three of those defects exacerbate disease symptoms. To reduce degradation, Bruce R. Donald of Duke University and coworkers used K*, a computational program they wrote, to design peptides capable of blocking binding between CFTR and CAL (CFTR-associated ligand), an interaction that promotes degradation. The predicted inhibitors bound CAL with high affinity and improved mutant CFTR function up to 12% in cultured cells from patients. Donald speculates that one of the inhibitors might work together with a different type of cystic fibrosis drug to boost CFTR activity in an additive way.
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