Modified vasoactive intestinal peptides
Inventors
Sadeghi, Homayoun • Dagher, Suzanne • Turner, Andrew
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9700598-B2
Publication Date
2017-07-11
Expiration Date
Abstract
The present invention provides modified Vasoactive Intestinal Peptides (VIPs), encoding polynucleotides and vectors, as well as pharmaceutical compositions comprising the same. The invention further provides methods of making and using the modified VIP agents. In accordance with the invention the VIP exhibits an extended circulatory half-life, receptor-binding or biological potency, and/or altered receptor binding profile with respect to unmodified VIP.
Core Innovation
The invention provides modified vasoactive intestinal peptide (VIP) therapeutics designed to act as VPAC2-selective receptor agonists. The compositions include a recombinant VPAC2-selective receptor agonist comprising the amino acid sequence of SEQ ID NO:13 with an N-terminal methionine that increases the preference of the agonist for VPAC2 versus VPAC1. The constructs are formulated as pharmaceutical compositions with pharmaceutically acceptable excipients for the treatment of heart disease.
A key feature is fusion of the VPAC2-selective agonist to an elastin-like polypeptide (ELP) at the C-terminus. The ELP prolongs the absorption phase from an injection site and extends the circulatory half-life. The ELP comprises at least 60 repeat units of VPGXG (SEQ ID NO:3), where X is independently selected from Val, Ala, and Gly.
The patent further specifies embodiments where the ELP includes defined compositions of X at a Val/Ala/Gly ratio and includes particular thresholds or counts of VPGXG units. It also describes related architectures using VIP sequence variants such as an alternative sequence (SEQ ID NO:14) and emphasizes receptor-binding preference, including VPAC2 versus VPAC1 selectivity.
Claims Coverage
The disclosed independent claims are directed to pharmaceutical compositions comprising a recombinant VPAC2-selective receptor agonist (SEQ ID NO:13 with N-terminal methionine) fused to an ELP (C-terminal) and formulated with pharmaceutically acceptable excipients. The inventive features focus on VPAC2 selectivity via N-terminal methionine, and pharmacokinetic/pharmacodynamic extension via C-terminal ELP containing at least 60 VPGXG repeat units with defined Val/Ala/Gly content.
VPAC2-selective VIP agonist with N-terminal methionine favoring VPAC2 over VPAC1
A recombinant VPAC2-selective receptor agonist comprising the amino acid sequence of SEQ ID NO:13 having an N-terminal methionine increasing the preference of the agonist for VPAC2 versus VPAC1.
C-terminal ELP prolonging absorption and extending circulatory half-life
An elastin-like polypeptide (ELP) at the C-terminus prolonging the absorption phase from an injection site and extending the circulatory half-life.
ELP with at least 60 VPGXG repeat units
The ELP comprises at least 60 repeat units of VPGXG (SEQ ID NO:3) where X is independently selected from Val, Ala, and Gly, with embodiments specifying a Val/Ala/Gly ratio.
Pharmaceutical composition for heart disease with pharmaceutically acceptable excipients
One or more pharmaceutically acceptable excipients in a pharmaceutical composition for the treatment of heart disease.
Across the independent claims, the coverage centers on a VPAC2-selective recombinant agonist based on SEQ ID NO:13 with an N-terminal methionine to increase VPAC2 over VPAC1, fused at the C-terminus to an ELP that prolongs absorption and extends circulatory half-life, where the ELP contains VPGXG repeats of at least 60 units with defined Val/Ala/Gly content.
Stated Advantages
Prolongs the absorption phase from an injection site.
Extends the circulatory half-life.
Increases the preference of the agonist for VPAC2 versus VPAC1.
Documented Applications
Treatment of heart disease, including myocardial fibrosis, heart failure, and cardiomyopathy.
Interested in licensing this patent?