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

Cromm PM, Schaubach S, Spiegel J, Fürstner A, Grossmann TN, Waldmann H - Nat Commun (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany.

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.

No MeSH data available.


Sequence and chemical structure of the engulfed bicyclic peptide 17.R, side chain of a proteinogenic amino acid except Cys or Met.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4834642&req=5

f4: Sequence and chemical structure of the engulfed bicyclic peptide 17.R, side chain of a proteinogenic amino acid except Cys or Met.

Mentions: In peptide 16, the two individual macrocycles are sequentially arranged along the amino acid chain, that is, the two individual macrocycles are linked by a linear amino acid sequence. A synthetically more challenging setup involves the synthesis of two entangled macrocyles resulting in more constrained peptide scaffolds (for example, peptide 17, Fig. 4). In this architecture, an edge-on bimacrocycle structure is generated as opposed to a linear macrocycle arrangement as in peptide 16. Most notably, entangled bicyclic peptide 17 (Fig. 4) was also efficiently formed in both the sequential as well as the one-pot synthesis (Supplementary Figs 11 and 12).


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

Cromm PM, Schaubach S, Spiegel J, Fürstner A, Grossmann TN, Waldmann H - Nat Commun (2016)

Sequence and chemical structure of the engulfed bicyclic peptide 17.R, side chain of a proteinogenic amino acid except Cys or Met.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834642&req=5

f4: Sequence and chemical structure of the engulfed bicyclic peptide 17.R, side chain of a proteinogenic amino acid except Cys or Met.
Mentions: In peptide 16, the two individual macrocycles are sequentially arranged along the amino acid chain, that is, the two individual macrocycles are linked by a linear amino acid sequence. A synthetically more challenging setup involves the synthesis of two entangled macrocyles resulting in more constrained peptide scaffolds (for example, peptide 17, Fig. 4). In this architecture, an edge-on bimacrocycle structure is generated as opposed to a linear macrocycle arrangement as in peptide 16. Most notably, entangled bicyclic peptide 17 (Fig. 4) was also efficiently formed in both the sequential as well as the one-pot synthesis (Supplementary Figs 11 and 12).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany.

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.

No MeSH data available.