Structure-Based Design of Non-Natural Amino Acid Inhibitors of Amyloid Fibrillation

• Published in: Nature (London) Vol. 475; no. 7354; pp. 96 - 100
• Main Authors: Sievers, Stuart A., Karanicolas, John, Chang, Howard W., Zhao, Anni, Jiang, Lin, Zirafi, Onofrio, Stevens, Jason T., Münch, Jan, Baker, David, Eisenberg, David
• Format: Journal Article
• Language: English
• Published: 15.06.2011
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10154

Many globular and natively disordered proteins can convert into amyloid fibers. These fibers are associated with numerous pathologies 1 as well as with normal cellular functions 2 , 3 , and frequently form during protein denaturation 4 , 5 . Inhibitors of pathological amyloid fibers could serve as leads for therapeutics, provided the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibers as templates, we have designed and characterized an all D-amino acid inhibitor of fibrillation of the tau protein found in Alzheimer’s disease, and a non-natural L-amino acid inhibitor of an amyloid fiber that enhances sexual transmission of HIV. Our results indicate that peptides from structure-based designs can disrupt the fibrillation of full-length proteins, including those like tau that lack fully ordered native structures.