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 Piazza, Joshua G. Whalen, Per Jr. Greisen, David W. Christianson and David Baker ()
Additional contact information
Parisa Hosseinzadeh: Institute for Protein Design
Paris R. Watson: University of Pennsylvania
Timothy W. Craven: Institute for Protein Design
Xinting Li: Institute for Protein Design
Stephen Rettie: Institute for Protein Design
Fátima Pardo-Avila: Stanford University School of Medicine
Asim K. Bera: Institute for Protein Design
Vikram Khipple Mulligan: Institute for Protein Design
Peilong Lu: Institute for Protein Design
Alexander S. Ford: Institute for Protein Design
Brian D. Weitzner: Institute for Protein Design
Lance J. Stewart: Institute for Protein Design
Adam P. Moyer: Institute for Protein Design
Maddalena Piazza: Institute for Protein Design
Joshua G. Whalen: Institute for Protein Design
Per Jr. Greisen: Institute for Protein Design
David W. Christianson: University of Pennsylvania
David Baker: Institute for Protein Design

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-23609-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23609-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-23609-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().