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Geometric diversity through permutation of backbone configuration in cyclic peptide libraries
Zachary E Perlman1, Jonathan E Bock, Jeffrey R Peterson
1Department of Systems Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115l, USA.
Bioorganic & Medicinal Chemistry Letters
|October 11, 2005
Summary
Cyclic peptide synthesis is influenced by ring size and proline content. Scaffold geometry plays a larger role than side chain variation in cyclization efficiency, leading to more potent actin assembly inhibitors.
Area of Science:
- Peptide chemistry
- Medicinal chemistry
- Structural biology
Background:
- Cyclic peptides offer diverse structures through modifications in ring size and residue placement.
- Parameters like D-amino acids and proline influence cyclic peptide conformations.
- Simple sequence changes can lead to structurally varied cyclic peptides.
Purpose of the Study:
- To synthesize and analyze a cyclic peptide library with varied ring size, stereochemistry, and proline placement.
- To investigate the impact of scaffold geometry versus side chain variation on cyclization efficiency.
- To apply these findings to develop improved cyclic peptide inhibitors of actin assembly.
Main Methods:
- Synthesis of a cyclic peptide library with variations in ring size, alpha-carbon stereochemistry, and proline position.
- Analysis of cyclization yields based on peptide size and proline content.
- Utilizing split-pool libraries to compare scaffold geometry and side chain effects.
- Developing cyclodimeric variants of an actin assembly inhibitor.
Main Results:
- Heptapeptides generally cyclized more efficiently than hexapeptides.
- Increased proline content correlated with decreased cyclization yields.
- Scaffold geometry was found to be a more significant factor than side chain variation in cyclization efficiency.
- Optimized cyclodimeric variants showed improved potency compared to the original inhibitor.
Conclusions:
- Cyclic peptide synthesis efficiency is predictable based on ring size and proline content.
- Scaffold design is crucial for optimizing cyclization and biological activity.
- This approach successfully generated enhanced cyclic peptide inhibitors for biological targets.
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