Modified vasoactive intestinal peptides
Inventors
Sadeghi, Homayoun • Dagher, Suzanne • Turner, Andrew
Assignees
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Publication Number
US-9029505-B2
Publication Date
2015-05-12
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 relates to modified vasoactive intestinal peptide (VIP) therapeutics, including recombinant VIP and chemical modifications, to achieve VPAC-selective receptor agonism. The background problem addressed is that native VIP therapeutics require improvement in circulatory half-life and receptor binding preference, specifically between VPAC2 and VPAC1. The description provides VPAC2-selective agonist constructs based on VIP sequence modifications and receptor-preference tuning.
In the recombinant VPAC2-selective receptor agonist, an N-terminal methionine modification is used with His1 of the VIP sequence at position 2 to increase the preference of the agonist for VPAC2 versus VPAC1. The agonist further includes an elastin-like polypeptide (ELP) at the C-terminus, and the ELP is described as prolonging the absorption phase from an injection site and extending circulatory half-life. The ELP is specified by VPGXG units and by composition ranges for X, together with structural features and transition temperature behavior described using inverse phase transition and transition temperature (Tt).
The document further supports these constructs with experimental examples demonstrating VPAC2 selectivity and extended pharmacokinetics, including in vivo blood pressure lowering with VIP-ELP fusions. The description includes named constructs such as PB1046, PB1047, PB1048, and PB1120, and includes pharmacokinetic profile and pharmacodynamic data in animal models, including TK data and blood pressure effects after administration and receptor activity evaluation in vitro.
Claims Coverage
Two independent claims are provided. Both claims define recombinant VPAC2-selective receptor agonists: one specifies an amino acid sequence with an N-terminal methionine/His position change and a C-terminal ELP with defined structural constraints, and the other defines a recombinant VPAC2-selective receptor agonist by an amino acid sequence corresponding to SEQ ID NO: 14.
N-terminal methionine with His at position 2 to increase VPAC2 preference
A recombinant VPAC2-selective receptor agonist comprising an amino acid sequence having an N-terminal methionine with His1 at position 2, increasing the preference of the agonist for VPAC2 versus VPAC1.
C-terminal elastin-like polypeptide with defined VPGXG unit number and X composition
A recombinant VPAC2-selective receptor agonist comprising an elastin-like polypeptide at the C-terminus prolonging the absorption phase from an injection site and extending the circulatory half-life, where the ELP has from 75 to 130 units of VPGXG and X is 40% to 60% Val, 10% to 30% Ala, and 20% to 40% Gly.
Sequence-defined recombinant VPAC2-selective receptor agonist
A recombinant VPAC2-selective receptor agonist comprising the amino acid sequence of SEQ ID NO: 14.
Overall, claim coverage centers on recombinant VPAC2-selective receptor agonists defined by VIP sequence modifications to increase VPAC2 preference and by C-terminal ELP fusion constrained by VPGXG unit count and X residue composition, with a second independent claim covering a sequence-defined VPAC2-selective receptor agonist comprising SEQ ID NO: 14.
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
Demonstrated in vivo blood pressure lowering with VIP-ELP fusions, including constructs such as PB1046, PB1047, and PB1120, after administration including single subcutaneous injection.
Pharmacokinetic and pharmacodynamic effects are reported using animal models, including TK data in monkeys and blood pressure effects in rats.
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