Cyclic peptides can engage a single binding pocket through highly divergent modes

Karishma Patel; Louise J Walport; James L Walshe; Paul D Solomon; Jason K K Low; Daniel H Tran; Kevork S Mouradian; Ana P G Silva; Lorna Wilkinson-White; Alexander Norman; Charlotte Franck; Jacqueline M Matthews; J Mitchell Guss; Richard J Payne; Toby Passioura; Hiroaki Suga; Joel P Mackay

doi:10.1073/pnas.2003086117

Cyclic peptides can engage a single binding pocket through highly divergent modes

Proc Natl Acad Sci U S A. 2020 Oct 27;117(43):26728-26738. doi: 10.1073/pnas.2003086117. Epub 2020 Oct 12.

Authors

Karishma Patel¹, Louise J Walport^{2

3

4}, James L Walshe¹, Paul D Solomon¹, Jason K K Low¹, Daniel H Tran⁵, Kevork S Mouradian¹, Ana P G Silva¹, Lorna Wilkinson-White⁶, Alexander Norman⁵, Charlotte Franck^{1

5}, Jacqueline M Matthews¹, J Mitchell Guss¹, Richard J Payne⁵, Toby Passioura^{1

4

5

6}, Hiroaki Suga⁷, Joel P Mackay⁸

Affiliations

¹ School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
² Protein-Protein Interaction Laboratory, The Francis Crick Institute, London NW1 1AT, United Kingdom; [email protected] [email protected] [email protected].
³ Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, United Kingdom.
⁴ Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
⁵ School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
⁶ Sydney Analytical Core Research Facility, The University of Sydney, NSW 2006, Australia.
⁷ Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan; [email protected] [email protected] [email protected].
⁸ School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia; [email protected] [email protected] [email protected].

Abstract

Cyclic peptide library screening technologies show immense promise for identifying drug leads and chemical probes for challenging targets. However, the structural and functional diversity encoded within such libraries is largely undefined. We have systematically profiled the affinity, selectivity, and structural features of library-derived cyclic peptides selected to recognize three closely related targets: the acetyllysine-binding bromodomain proteins BRD2, -3, and -4. We report affinities as low as 100 pM and specificities of up to 10⁶-fold. Crystal structures of 13 peptide-bromodomain complexes reveal remarkable diversity in both structure and binding mode, including both α-helical and β-sheet structures as well as bivalent binding modes. The peptides can also exhibit a high degree of structural preorganization. Our data demonstrate the enormous potential within these libraries to provide diverse binding modes against a single target, which underpins their capacity to yield highly potent and selective ligands.

Keywords: BET bromodomain inhibition; BRD3; BRD4; de novo cyclic peptides; structural biology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Drug Discovery
Humans
Peptide Library*
Peptides, Cyclic* / chemistry
Peptides, Cyclic* / metabolism
Protein Binding
Protein Domains
Transcription Factors / chemistry
Transcription Factors / metabolism

Substances

BRD2 protein, human
BRD3 protein, human
Peptide Library
Peptides, Cyclic
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding