A survey of stapling methods to increase affinity, activity, and stability of ghrelin analogues

Esteban, Juan J.; Mason, Julia R.; Kaminski, Jakob; Ramachandran, Rithwik; Luyt, Leonard G.

doi:10.1039/d3md00441d

RSC Med. Chem.

2024

DOI: 10.1039/d3md00441d

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A survey of stapling methods to increase affinity, activity, and stability of ghrelin analogues

Juan J. Esteban,

Julia R. Mason,

Jakob Kaminski

et al.

Abstract: In this paper we present a survey of stapling methods for the peptide ghrelin, resulting in the discovery of ghrelin analogues with improved affinity, stability and efficacy.

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Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics

Swenson,

Mandava,

Thomas

et al. 2024

Chem. Rev.

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The development of potent, specific, and pharmacologically viable chemical probes and therapeutics is a central focus of chemical biology and therapeutic development. However, a significant portion of predicted disease-causal proteins have proven resistant to targeting by traditional small molecule and biologic modalities. Many of these so-called "undruggable" targets feature extended, dynamic protein−protein and protein−nucleic acid interfaces that are central to their roles in normal and diseased signaling pathways. Here, we discuss the development of synthetically stabilized peptide and protein mimetics as an everexpanding and powerful region of chemical space to tackle undruggable targets. These molecules aim to combine the synthetic tunability and pharmacologic properties typically associated with small molecules with the binding footprints, affinities and specificities of biologics. In this review, we discuss the historical and emerging platforms and approaches to design, screen, select and optimize synthetic "designer" peptidomimetics and synthetic biologics. We examine the inspiration and design of different classes of designer peptidomimetics: (i) macrocyclic peptides, (ii) side chain stabilized peptides, (iii) non-natural peptidomimetics, and (iv) synthetic proteomimetics, and notable examples of their application to challenging biomolecules. Finally, we summarize key learnings and remaining challenges for these molecules to become useful chemical probes and therapeutics for historically undruggable targets.

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Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics

Swenson,

Mandava,

Thomas

et al. 2024

Chem. Rev.

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show abstract

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A survey of stapling methods to increase affinity, activity, and stability of ghrelin analogues

Abstract: In this paper we present a survey of stapling methods for the peptide ghrelin, resulting in the discovery of ghrelin analogues with improved affinity, stability and efficacy.

Cited by 1 publication

References 50 publications

Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics

Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics

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