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Publication Number
US-10854312-B2
Publication Date
2020-12-01
Expiration Date
Abstract
Methods and compositions related to the selective, specific disruption of multiple ligand-receptor signaling interactions, such as ligand-receptor interactions implicated in disease, are disclosed. These interactions may involve multiple cytokines in a single receptor family or multiple ligand receptor interactions from at least two distinct ligand-receptor families. The compositions may comprise polypeptides having composite sequences that comprise sequence fragments of two or more ligand binding sites. The methods and compositions may involve sequence fragments of two or more ligand binding sites that are arranged to conserve the secondary structure of each of the ligands from which the sequence fragments were taken.
Core Innovation
The invention relates to selective peptide antagonists that disrupt multiple ligand–receptor signaling interactions by providing composite inhibitor polypeptides constructed from sequence fragments of multiple ligand binding interfaces while conserving ligand secondary structure. The composite inhibitor polypeptides are therapeutic composite peptides that inhibit cytokine activity for cytokines selected from a family of cytokines that bind to a common receptor.
A disclosed problem is that cytokines within a shared receptor signaling context act through common receptor interactions, so inhibiting undesired members risks insufficient selectivity. The disclosed approach is to target selected members only by identifying specific amino acids and structurally conserved regions responsible for binding of each cytokine to the common receptor, and designing candidate composite peptides that contain the specific amino acids and the structurally conserved regions.
Cross-family inhibitory polypeptides are further disclosed by linking at least two therapeutic composite peptides via a linker, where each composite peptide is designed to inhibit at least two cytokines selected from cytokine families that bind to a common receptor. The document provides examples and discussion including BNZ132-1 and a cross-family construct BNZ132-PEG-130 that links a BNZ132-1–derived component with an IL-6-family inhibitor component, and extends design discussions to IL-6 and IL-17 families.
Claims Coverage
The document contains two independent claims (clm-00001 and clm-00009). Across these independent claims, the core coverage centers on cross-family inhibitory polypeptides that include at least two therapeutic composite peptides linked by a linker, where each composite peptide is designed to inhibit cytokine activity for multiple cytokines within families binding to a common receptor.
Cross-family inhibitory polypeptide with linked therapeutic composite peptides
A cross-family inhibitory polypeptide comprising at least two therapeutic composite peptides linked via a linker, wherein each therapeutic composite peptide inhibits an activity of at least two cytokines selected from a family of cytokines that bind to a common receptor.
Computationally derived composite peptides for common receptor cytokine binding
Each therapeutic composite peptide is produced by obtaining amino acid sequences of at least two cytokines from an amino acid sequence database, generating 3D renditions of receptor binding interactions for cytokines binding to a common receptor via computer-assisted docking simulations and/or analyzing crystal structures of cytokines and the common receptor, identifying specific amino acids and structurally conserved regions responsible for binding, designing candidate composite peptides containing the specific amino acids and structurally conserved regions, screening for thermodynamic stability and proper binding, synthesizing candidate composite peptides, testing for binding and biological activity, and identifying therapeutic composite peptides.
Family scope restricted to γc-family, IL-6 family, and IL-17 family cytokines
Inhibits an activity of at least two cytokines selected from a family of cytokines that bind to a common receptor, wherein the family is selected from the group consisting of γc-family of cytokines, IL-6 family of cytokines, and IL-17 family of cytokines.
Composite peptide region alignment with specified SEQ ID NO regions and linker
Each therapeutic composite peptide comprises a region 1-20 amino acids in length that aligns with a corresponding region of a target ligand or receptor having a sequence of any one of SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ m NO:148, SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:158, SEQ NO:159, SEQ ID NO:160, and SEQ ID NO:161, and wherein the at least two therapeutic composite peptides are linked via a linker.
The independent claims collectively require cross-family inhibitory polypeptides containing multiple therapeutic composite peptides linked by a linker, with inhibition of multiple cytokines that bind to a common receptor. One independent claim additionally requires a computational workflow using amino-acid sequence databases, 3D receptor-binding interaction renditions (docking and/or crystal structure analysis), identification of binding amino acids and structurally conserved regions, candidate design, stability and binding screening, synthesis, and testing to produce the therapeutic composite peptides.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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