Peptides comprising non-natural amino acids and methods of making and using the same
Inventors
Shandler, Scott • Gellman, Samuel H. • Gledhill, John M.
Assignees
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Publication Number
US-10543255-B2
Publication Date
2020-01-28
Expiration Date
Abstract
This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an α-amino acid and at least one β-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived.
Core Innovation
The patent describes VIP-derived α/β23 helical polypeptide analogs of vasoactive intestinal peptide (VIP) in which α-to-β23 replacements incorporate non-natural residue(s) to produce peptides with VPAC1 and VPAC2 receptor activity. The described analogs include peptides defined by SEQ ID NO:17 and SEQ ID NO:18, each having exactly one amino acid substitution where the substituted residue is a non-naturally occurring amino acid residue.
The disclosure defines the structural scope of β-amino acid residues within VIP/VIP-analog peptides, including cyclic non-natural β-amino acid residues such as ACHC and ACPC, and broader classes of β-amino acids defined by general Formula I. Terminal modifications include N-acylation, optional C-terminal amidation, N-terminal acetylation, and optional PEGylation with polyethylene glycol attached via specified covalent attachments.
The disclosure presents structural and characterization studies for the VIP analog design rationale, including circular dichroism and NMR structural analysis, stability assessments including in-vitro and ex-vivo stability as well as microsome, in-vivo stability, and bioavailability characterization [procedural detail omitted for safety]. In addition, the document provides in-vitro functional and receptor characterization using cAMP modulation assays, competitive binding using 125I-labeled tracers, and receptor-functional characterization such as internalization using a PathHunter internalization assay.
The overall described approach is to create VIP analogs with non-natural residue incorporation to support protease resistance and half-life extension while maintaining bioactivity through VPAC receptor engagement. The invention is positioned around receptor-selective VIP-family peptide analogs and related therapeutic use, receptor activity modulator identification assays, and imaging with PET/MRI using imaging agents.
Claims Coverage
The partial claim set includes two independent claims, each directed to a peptide defined by a specific SEQ ID NO (SEQ ID NO:17 or SEQ ID NO:18) with exactly one non-naturally occurring amino acid substitution. Dependent claims further define the substitution chemistry as alpha-to-beta homo amino acid, constrain the substitution position within amino acid ranges, add N-terminal acetylation and C-terminal primary amidation, and claim pharmaceutical compositions and a method inhibiting TNF-α secretion by administering the composition.
Single non-naturally occurring amino-acid substitution in a SEQ ID NO:17 peptide
A peptide comprising SEQ ID NO:17 or SEQ ID NO:17 consisting of one amino acid substitution, wherein the amino acid substitution is a non-naturally occurring amino acid residue.
Single non-naturally occurring amino-acid substitution in a SEQ ID NO:18 peptide
A peptide comprising SEQ ID NO:18 consisting of one amino acid substitution, wherein the substitution is a non-naturally occurring amino acid residue.
Alpha-to-beta homo amino-acid substitution chemistry
The peptide wherein the amino acid substitution is an alpha amino acid replaced with a beta homo amino acid.
Substitution location constrained within SEQ ID NO:17
The peptide in which the substitution occurs at amino acid positions 10 through 19 of SEQ ID NO:17.
Substitution location constrained within SEQ ID NO:18
The peptide in which the substitution is positioned between amino acid positions 10 and 19 of SEQ ID NO:18.
N-terminal acetylation and C-terminal primary amidation
The peptide that, in addition to the substitution, has an acetyl group at the N-terminus and a primary amide at the C-terminus.
Pharmaceutical composition including the peptide and a pharmaceutically acceptable carrier
A pharmaceutical composition containing the peptide together with a pharmaceutically acceptable carrier.
Method of inhibiting TNF-α secretion by administering the pharmaceutical composition
A method inhibiting TNF-α secretion in a subject by administering the pharmaceutical composition.
Across the two independent claims, the core claimed inventive theme is a peptide defined by a specific SEQ ID NO (SEQ ID NO:17 or SEQ ID NO:18) that includes exactly one amino acid substitution using a non-naturally occurring amino acid residue. Dependent claims further define the substitution chemistry, constrain the substitution position, add N-terminal acetylation and C-terminal primary amidation, and claim pharmaceutical compositions and a method inhibiting TNF-α secretion by administering the composition.
Stated Advantages
Improved stability-related properties are described in support of the analog design rationale, including protease resistance and half-life extension.
Bioactivity is intended to be maintained through VPAC receptor engagement.
Engineered to resist degradation.
Designed to increase half-life.
Preserves receptor binding and selectivity across VPAC1/VPAC2/PAC1.
Documented Applications
Prophetic in-vivo cancer xenograft model testing using VIP or VIP analog dosing with tumor growth monitoring and plasma VIP/cAMP sampling [procedural detail omitted for safety].
Disease-model testing including arthritis, colitis, Parkinson’s disease, and additional in-vivo functional determination in diabetic nephropathy [procedural detail omitted for safety].
Method context claimed as inhibiting TNF-α secretion in a subject by administering the pharmaceutical composition.
Therapeutic use for pulmonary hypertension.
Therapeutic use for autoimmune/inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.
Therapeutic use for cancer and cancer cell growth inhibition.
Selective tumor targeting of VPAC1-overexpressing cells with covalently linked chemotherapeutic payloads using cleavable linkers.
Receptor activity modulator identification assays.
Imaging with PET/MRI using imaging agents.
Pharmaceutical compositions and medicaments for diseases.
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