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Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites

Journal Article · · Nature Communications
 [1];  [2];  [1];  [1];  [3];  [4];  [1];  [1];  [1];  [1];  [1];  [1];  [5];  [1];  [1];  [1];  [2];  [1]
  1. Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry. Inst. for Protein Design
  2. Univ. of Pennsylvania, Philadelphia, PA (United States). Roy and Diana Vagelos Lab. Dept. of Chemistry
  3. Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry. Inst. for Protein Design. Molecular and Cellular Biology Ph.D. Program
  4. Stanford Univ. School of Medicine, CA (United States). Dept. of Structural Biology
  5. Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry. Inst. for Protein Design. Molecular Engineering Ph.D. Program
Despite recent success in computational design of structured cyclic peptides, de novo design of cyclic peptides that bind to any protein functional site remains difficult. To address this challenge, we develop a computational “anchor extension” methodology for targeting protein interfaces by extending a peptide chain around a non-canonical amino acid residue anchor. To test our approach using a well characterized model system, we design cyclic peptides that inhibit histone deacetylases 2 and 6 (HDAC2 and HDAC6) with enhanced potency compared to the original anchor (IC50 values of 9.1 and 4.4 nM for the best binders compared to 5.4 and 0.6 µM for the anchor, respectively). The HDAC6 inhibitor is among the most potent reported so far. These results highlight the potential for de novo design of high-affinity protein-peptide interfaces, as well as the challenges that remain.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
SC0012704
OSTI ID:
1812055
Alternate ID(s):
OSTI ID: 1875646
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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