Journal Article

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

Greisen, Per Jr, Moyer, Adam P., Craven, Timothy W., Baker, David, Watson, Paris R., Ford, Alexander S., Whalen, Joshua G., Pardo-Avila, Fátima, Di Piazza, Maddalena, Weitzner, Brian D., Mulligan, Vikram Khipple, Rettie, Stephen, Lu, Peilong, Li, Xinting, Bera, Asim K., Hosseinzadeh, Parisa, Stewart, Lance J., Christianson, David W.

2021

Overview

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 (IC 50 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. Cyclic peptides are of particular interest due to their pharmacological properties, but their design for binding to a target protein is challenging. Here, the authors present a computational “anchor extension” methodology for de novo design of cyclic peptides that bind to the target protein with high affinity, and validate the approach by developing cyclic peptides that inhibit histone deacetylases 2 and 6.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/58 / 140/131 / 631/114/469 / 639/638/45/611 / 82/16 / 82/58 / 82/83 / Affinity / Amino acids / BASIC BIOLOGICAL SCIENCES / Binders / Catalytic Domain - drug effects / Computer applications / Crystallography, X-Ray / Design / Drug Design / Enzyme Assays / HDAC2 protein / Histone deacetylase / 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 / Histones / Humanities and Social Sciences / Inhibitory Concentration 50 / Interfaces / Molecular Docking Simulation / multidisciplinary / Nuclear Magnetic Resonance, Biomolecular / Peptide Library / Peptides / Peptides, Cyclic - chemistry / Peptides, Cyclic - pharmacology / protein design / Proteins / Recombinant Proteins - genetics / Recombinant Proteins - isolation & purification / Recombinant Proteins - metabolism / Recombinant Proteins - ultrastructure / Science / Science (multidisciplinary) / Structure-Activity Relationship / Zebrafish Proteins - genetics / Zebrafish Proteins - ultrastructure