Cyclic Peptide Design Methods

Increasingly, cyclic peptides are being used in the therapeutic area. In the last two decades, cyclic peptides have been developed as small molecules with high binding affinities and low metabolic toxicity, and as antibodies with good stability and ease of manufacture.

Peptides are a promising class of drugs to target protein surfaces that are difficult to target using small molecules2,3. Cyclic peptides, characterized by rigid structures, are synthesized by disulfide bonding two Cys residues or chemical linkers. They also have a diverse peptide sequence that can serve as a binding motif toward receptors and other proteins.

Library-based peptide discovery methods are widely used to develop cyclic peptides that can bind proteins with high affinity4,8,9. Recent advances in library size, amino acid incorporation and cyclization chemistry17,18,19 have led to a variety of cyclic peptides being designed for a wide range of applications, including inhibitors against proteasome, HIV integrase, and phosphatase.

The synthesis of cyclic peptides with high sequence diversity is a challenge. The most efficient synthesis of cyclic peptides has been achieved using split-and-pool synthesis.

Libraries based on split-and-pool synthesis allow the screening of cyclic peptides with on-bead screening, in-solution screening and microarray screening for biological activity with high throughput (Sweeney and Pei, 2003; Joo et al., 2006). In addition, spatial segregation of cyclic peptides on the bead surface allows high-throughput sequence determination for binding to the target molecules with partial Edman degradation, compared to automated Edman analysis (Thakkar et al., 2006).

To explore a larger skeletal diversity of cyclic peptides, we generated macrocycles using design methods 3 and 4 by extending the SHA-Trp dimer to form closed macrocycles with additional amino acids. We sampled around 100,000 macrocycles and selected around 100 with best shape complementarity and G of binding for downstream conformational sampling analysis.


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