Cyclic peptides can engage a single binding pocket through highly divergent modes
Karishma Patel1, Louise J Walport2,3,4, James L Walshe1
1School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
Summary
Cyclic peptide libraries can yield potent drug leads. This study characterized peptide-protein interactions, revealing diverse structures and binding modes for bromodomain targets, enabling highly selective ligand discovery.
Area of Science:
- Chemical Biology
- Structural Biology
- Drug Discovery
Background:
- Cyclic peptide libraries are promising for drug lead and chemical probe discovery.
- The structural and functional diversity within these libraries remains largely undefined.
Purpose of the Study:
- To systematically profile the affinity, selectivity, and structural features of cyclic peptides targeting bromodomain proteins (BRD2, -3, and -4).
- To understand the structural diversity and binding modes of library-derived cyclic peptides.
Main Methods:
- Systematic profiling of affinity and selectivity.
- Crystal structure determination of 13 peptide-bromodomain complexes.
- Analysis of structural features, including secondary structures and binding modes.
Main Results:
- Identified cyclic peptides with affinities as low as 100 pM and specificities up to 10^6-fold.
- Revealed remarkable structural diversity, including alpha-helical and beta-sheet structures, and bivalent binding modes.
- Observed high structural preorganization in some peptides.
Conclusions:
- Cyclic peptide libraries offer vast potential for discovering potent and selective ligands.
- Diverse binding modes against a single target can be achieved, facilitating the development of targeted therapeutics.
- This work provides a foundation for understanding and leveraging cyclic peptide libraries in drug discovery.
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