PUBLICATION
Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites
- Authors
- Hosseinzadeh, P., Watson, P.R., Craven, T.W., Li, X., Rettie, S., Pardo-Avila, F., Bera, A.K., Mulligan, V.K., Lu, P., Ford, A.S., Weitzner, B.D., Stewart, L.J., Moyer, A.P., Di Piazza, M., Whalen, J.G., Greisen, P.J., Christianson, D.W., Baker, D.
- ID
- ZDB-PUB-210616-1
- Date
- 2021
- Source
- Nature communications 12: 3384 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Catalytic Domain/drug effects
- Crystallography, X-Ray
- Drug Design*
- Enzyme Assays
- Histone Deacetylase 2/antagonists & inhibitors
- Histone Deacetylase 2/isolation & purification
- Histone Deacetylase 2/metabolism
- Histone Deacetylase 2/ultrastructure
- Histone Deacetylase 6/antagonists & inhibitors
- Histone Deacetylase 6/genetics
- Histone Deacetylase 6/isolation & purification
- Histone Deacetylase 6/ultrastructure
- Histone Deacetylase Inhibitors/chemistry
- Histone Deacetylase Inhibitors/pharmacology*
- Inhibitory Concentration 50
- Molecular Docking Simulation
- Nuclear Magnetic Resonance, Biomolecular
- Peptide Library
- Peptides, Cyclic/chemistry
- Peptides, Cyclic/pharmacology*
- Recombinant Proteins/genetics
- Recombinant Proteins/isolation & purification
- Recombinant Proteins/metabolism
- Recombinant Proteins/ultrastructure
- Structure-Activity Relationship*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/ultrastructure
- PubMed
- 34099674 Full text @ Nat. Commun.
Citation
Hosseinzadeh, P., Watson, P.R., Craven, T.W., Li, X., Rettie, S., Pardo-Avila, F., Bera, A.K., Mulligan, V.K., Lu, P., Ford, A.S., Weitzner, B.D., Stewart, L.J., Moyer, A.P., Di Piazza, M., Whalen, J.G., Greisen, P.J., Christianson, D.W., Baker, D. (2021) Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites. Nature communications. 12:3384.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping