Macrocyclic Polypeptides with L/D Amino Acids
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Solution Overview
Problem
Current approaches to designing macrocyclic peptides are limited by the difficulty in systematically searching the structural space spanned by such compounds, as natural proteins do not provide useful guides for regular secondary structures and hydrophobic cores, and existing methods struggle to repurpose macrocycles for new functions.
Innovation Solution
The development of macrocyclic polypeptides comprising up to 3 amino acid substitutions compared to a reference sequence, incorporating both L and D amino acids, which are designed to fold into stable structures through near exhaustive backbone sampling and energy landscape calculations, enabling the identification of over 200 designs that can serve as starting points for therapeutics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If natural proteins are used as guides for macrocycle design, then the design process is simplified, but natural proteins do not provide useful guides for regular secondary structures and hydrophobic cores
Solution Approach 1:
The patent changes the fundamental parameters of amino acid chirality by incorporating both L and D amino acids in specific patterns, enabling the formation of regular secondary structures and hydrophobic cores that are not accessible with natural L-amino acids alone. This parameter change allows systematic exploration of macrocycle structural space while maintaining designability.
Solution Approach 2:
The patent creates composite macrocyclic structures by combining L and D amino acid residues in defined sequences, producing hybrid structures that exhibit both regular secondary structures and hydrophobic cores. These composite structures overcome the limitations of natural proteins as design guides while expanding structural versatility.
2Adaptability or versatility
If random library selection methods are used, then a wide range of sequences can be explored, but only a small fraction of the vast sequence space is covered and peptides are not structured in the absence of target
Solution Approach 1:
The patent applies preliminary structural design by calculating energy landscapes and identifying low-energy conformations before target binding. This preliminary action ensures that macrocycles are pre-structured with regular secondary structures and hydrophobic cores, enabling them to maintain stability in the absence of target while still exploring diverse sequence space through systematic L/D amino acid combinations.
3Stability of the object's composition
If few amino acid substitutions are allowed compared to reference sequences, then the design process is constrained, but this limitation enables identification of stable folded structures
Solution Approach 1:
The patent introduces asymmetry through the strategic placement of D-amino acid residues alongside L-amino acids, creating chiral patterns that stabilize specific folded structures. This asymmetric design allows constrained substitution (maintaining stability) while generating diverse macrocycle structures through different L/D arrangement patterns in the sequence.
Data Source
AI summary
Disclosed herein are macrocyclic polypeptides having no more than 3 ammo acid substitutions compared to the amino acid sequence of any one of SEQ ID NO: 1-2.37 or a mirror image thereof, wherein the polypeptide includes both L and D amino acids, libraries of such polypeptides, and uses thereof.