Structure-Based Design of Non-Natural Amino Acid Inhibitors of Amyloid Fibrillation
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 l...
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| Published in | Nature (London) Vol. 475; no. 7354; pp. 96 - 100 |
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| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
15.06.2011
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| Online Access | Get full text |
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| Abstract | 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. |
|---|---|
| AbstractList | 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. |
| Author | Karanicolas, John Baker, David Zhao, Anni Sievers, Stuart A. Chang, Howard W. Zirafi, Onofrio Jiang, Lin Eisenberg, David Stevens, Jason T. Münch, Jan |
| AuthorAffiliation | 1 Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 2 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 3 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 4 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany |
| AuthorAffiliation_xml | – name: 1 Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 – name: 2 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 – name: 4 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany – name: 3 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 |
| Author_xml | – sequence: 1 givenname: Stuart A. surname: Sievers fullname: Sievers, Stuart A. organization: Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany – sequence: 2 givenname: John surname: Karanicolas fullname: Karanicolas, John organization: Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany – sequence: 3 givenname: Howard W. surname: Chang fullname: Chang, Howard W. organization: Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany – sequence: 4 givenname: Anni surname: Zhao fullname: Zhao, Anni organization: Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany – sequence: 5 givenname: Lin surname: Jiang fullname: Jiang, Lin organization: Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany – sequence: 6 givenname: Onofrio surname: Zirafi fullname: Zirafi, Onofrio organization: Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany – sequence: 7 givenname: Jason T. surname: Stevens fullname: Stevens, Jason T. organization: Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany – sequence: 8 givenname: Jan surname: Münch fullname: Münch, Jan organization: Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany – sequence: 9 givenname: David surname: Baker fullname: Baker, David organization: Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany – sequence: 10 givenname: David surname: Eisenberg fullname: Eisenberg, David organization: Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles CA 90095-1570 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Center for Bioinformatics and Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence KS 66045-7534 Institute of Molecular Virology, University Hospital Ulm, Meyerhofstrasse 1, 89081, Ulm, Germany |
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1
as well as with normal... |
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| Title | Structure-Based Design of Non-Natural Amino Acid Inhibitors of Amyloid Fibrillation |
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