Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides

Abstract

Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures is limited due to a lack of appropriate orthogonal ring-closing reactions. Here, we report chemically orthogonal ring-closing olefin (RCM) and alkyne metathesis (RCAM), which enable an efficient chemo- and regioselective synthesis of complex bicyclic peptide scaffolds with variable macrocycle geometries. We also demonstrate that the formed alkyne macrocycle can be functionalized subsequently. The orthogonal RCM/RCAM system was successfully used to evolve a monocyclic peptide inhibitor of the small GTPase Rab8 into a bicyclic ligand. This modified peptide shows the highest affinity for an activated Rab GTPase that has been reported so far. The RCM/RCAM-based formation of bicyclic peptides provides novel opportunities for the design of bioactive scaffolds suitable for the modulation of challenging protein targets.

Protease-Resistant and Cell-Permeable Double-Stapled Peptides Targeting the Rab8a GTPase

“…[6][7][8] Members of this subfamily are implicated in a number of human diseases rendering them attractive targets in drug discovery [9][10][11] with only few synthetic modulators of activity reported so far. 4,[12][13][14] Peptides represent a promising compound class for the inhibition of challenging PPIs, as they have the ability to explore large interaction surfaces. 15,16 Recent examples demonstrate the potential of macrocyclic peptides as inhibitors of small GTPase PPIs.…”

“…[17][18][19][20][21] In this context, we reported hydrocarbon stapled peptides as the first direct modulators of a Rab GTPase in its activated GppNHp-bound form. 4,14 The peptide StRIP3 represents the best-characterized derivative, which binds Rab8a(GppNHp) with moderate affinity and is able to inhibit a Rab8a PPI in vitro.…”

Cross‐Metathesis on Immobilized Substrates – Application to the Generation of Synthetically and Biologically Relevant Structures

“…[99,100] We believe that we shall see the SP cross-variant of the reaction in the near future. There are many examples, from the SP synthesis of complex oligosaccharides and peptides to the preparation of biologically relevant small-molecule compounds, natural products included.…”

Bridged bicyclic peptides: Structure and function

“…Alkyne‐ and alkene‐RCM approaches have been combined to generate bicyclic peptides containing different unsaturated linkages with varied geometric constraints. GTPase‐targeting bicyclic peptide 34 has a bridged structure formed by two ring closing metathesis processes (Figure ) . The ring closing alkyne and olefin metathesis reactions were completed in one‐pot using a combination of a Mo‐complex and Grubb's first‐generation catalyst.…”