Mixed Chirality Peptide Macrocycles for Cyclic Symmetry
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Solution Overview
Problem
Cyclic symmetry is rare in single-chain proteins and peptides due to incompatibility with free N and C termini, limiting therapeutic and nanomaterial design opportunities.
Innovation Solution
Design and synthesis of polypeptides with high identity to specific amino acid sequences featuring cyclic and improper rotational symmetries, using 2-aminoisobutyric acid and maintaining chirality, which can be conjugated with metals and additional components for therapeutic and nanomaterial applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If cyclic symmetry is introduced into single-chain peptides, then structural rigidity and symmetry are improved, but compatibility with free N and C termini deteriorates
Solution Approach 1:
The peptide chain is divided into multiple identical or similar segments that are arranged symmetrically. Each segment contains specific amino acid residues that repeat in a defined pattern, creating cyclic symmetry while maintaining the ability to form closed macrocyclic structures with free termini compatibility through the segmented design.
Solution Approach 2:
The peptide adopts a nested structural organization where repeating segments are arranged in a hierarchical manner, with each segment containing sub-structural elements that contribute to the overall cyclic symmetry. This nesting allows the structure to achieve rigidity through internal organization while the outer layer maintains flexibility for terminus compatibility.
2Shape
If mixed chirality amino acids are used, then symmetric structure formation is improved, but manufacturing complexity increases
Solution Approach 1:
Different chirality configurations are assigned to specific local positions within the peptide sequence rather than uniformly throughout. The sequence contains designated sites for L-amino acids, D-amino acids, and achiral residues in specific patterns that create symmetry while simplifying synthesis by limiting chirality changes to predetermined locations.
Solution Approach 2:
The peptide design utilizes systematic variation of chirality parameters at specific positions to achieve symmetric structures. By changing the chirality state (L/D configuration) at defined residues and maintaining achiral residues at symmetry-critical positions, the structure achieves the desired symmetry without requiring complex manufacturing procedures.
3Reliability
If high sequence identity to reference peptides is maintained, then therapeutic applicability is improved, but structural innovation is limited
Solution Approach 1:
The peptide design incorporates a universal repeating unit that can be configured in multiple symmetric arrangements (different numbers of repeats, different chirality patterns). This universal motif maintains high sequence identity to reference peptides for therapeutic compatibility while allowing structural variation through different repeat configurations and symmetry operations.
Solution Approach 2:
The peptide is constructed as a composite of multiple amino acid types (chiral and achiral residues) arranged in a symmetric pattern. This composite structure combines familiar peptide sequences for therapeutic applicability with innovative symmetric architectures that provide new structural functionality and versatility.
Data Source
AI summary
The disclosure provides polypeptide comprising or consisting of an amino acid sequence at least 66%, 70%, 75%, 80%, 82%, 84%, 86%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NO: 1-91 as shown in Table I, wherein: (a) amino acid residues in upper case are L amino acids, and residues in lower case are D amino acids; (b) X is 2-aminoisobutyric acid (ATB); (c) no amino acid changes at proline or AIB e residues in the reference peptide are permitted; and (d) any amino acid changes must maintain chirality relative to the reference peptide.