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

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

doi:10.1038/s41467-021-23609-8

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

Nat Commun. 2021 Jun 7;12(1):3384. doi: 10.1038/s41467-021-23609-8.

Authors

Parisa Hosseinzadeh^{1

2}, Paris R Watson^#³, Timothy W Craven^#¹, Xinting Li^#¹, Stephen Rettie^#^{1

4}, Fátima Pardo-Avila⁵, Asim K Bera¹, Vikram Khipple Mulligan^{1

6}, Peilong Lu^{1

7}, Alexander S Ford¹, Brian D Weitzner^{1

8}, Lance J Stewart¹, Adam P Moyer^{1

9}, Maddalena Di Piazza¹, Joshua G Whalen¹, Per Jr Greisen^{1

10}, David W Christianson³, David Baker¹¹

Affiliations

¹ University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA.
² Knight Campus Center, University of Oregon, Eugene, OR, USA.
³ Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Molecular and Cellular Biology Ph.D. Program, University of Washington, Seattle, WA, USA.
⁵ Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Systems Biology, Center for Computational Biology, Flatiron Institute, New York, NY, USA.
⁷ Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China.
⁸ Lyell Immunopharma, Inc., Seattle, WA, USA.
⁹ Molecular Engineering Ph.D. Program, University of Washington, Seattle, WA, USA.
¹⁰ Novo Nordisk A/S, Måløv, Denmark.
¹¹ University of Washington, Department of Biochemistry, Institute for Protein Design, Seattle, WA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

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

Substances

Histone Deacetylase Inhibitors
Peptide Library
Peptides, Cyclic
Recombinant Proteins
Zebrafish Proteins
HDAC2 protein, human
HDAC6 protein, human
HDAC6 protein, zebrafish
Histone Deacetylase 2
Histone Deacetylase 6

Abstract

Publication types

MeSH terms

Substances

Grants and funding