Use of modified vasoactive intestinal peptides in the treatment of hypertension
Inventors
Georgopoulos, Lynne M. • Arnold, Susan
Assignees
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Publication Number
US-9561262-B2
Publication Date
2017-02-07
Expiration Date
Abstract
The present invention is based on the discovery that a VIP having a binding preference for VPAC2 can provide long-acting blood pressure control synergistically with concomitant anti-hypertensive therapies. Accordingly, methods and compositions useful for the treatment and/or amelioration of hypertension are provided.
Core Innovation
The invention provides a method for treating hypertension by administering a vasoactive intestinal peptide (VIP) having a binding preference for the Vasoactive Intestinal Peptide Receptor 2 (VPAC2) together with at least one anti-hypertensive drug selected from an α1 receptor antagonist, an ACE inhibitor, and a calcium channel blocker. The VIP comprises the amino acid sequence of SEQ ID NO: 13 with the N-terminal His at position 2 and an N-terminal methionine, and includes an elastin-like peptide (ELP) at the C-terminus.
The ELP comprises at least 90 repeats of VPGXG (SEQ ID NO: 3), and the VIP is described as demonstrating an extended half-life in circulation. The co-administration of the VIP and the anti-hypertensive drug is stated to produce a synergistic increase in long-lasting blood pressure control compared to administering VIP alone.
The disclosed VIP-ELP constructs are further described as optionally including an N-terminally modified SEQ ID NO:13 variant and/or an ELP-fused construct, for example an ELP1-120 fusion. The ELP structural design is described using VPGXG repeat motifs to support extended circulation half-life, and the combined regimen is reported as providing long-acting and synergistic blood pressure control.
Claims Coverage
The patent includes two independent claims, a method claim and a pharmaceutical composition claim. Both claims share the same core combination: a VPAC2-preferential VIP construct with specified SEQ ID NO: 13 and an ELP C-terminus comprising at least 90 VPGXG repeats, together with at least one selected anti-hypertensive drug, where co-administration provides synergistic, long-lasting blood pressure control compared to VIP alone.
VPAC2-preferential VIP fused with C-terminal elastin-like peptide and anti-hypertensive co-administration
Administering to a patient a vasoactive intestinal peptide (VIP) having a binding preference for VPAC2, where the VIP comprises the amino acid sequence of SEQ ID NO: 13 with the N-terminal His at position 2 and an N-terminal methionine and an elastin-like peptide (ELP) at the C-terminus, wherein the ELP comprises at least 90 repeats of VPGXG (SEQ ID NO: 3), the VIP demonstrates an extended half-life in circulation, and the VIP is co-administered with at least one anti-hypertensive drug selected from an α1 receptor antagonist, an ACE inhibitor, and a calcium channel blocker to produce a synergistic increase in long-lasting blood pressure control compared to administering VIP alone.
VPAC2-preferential VIP construct in a pharmaceutical composition for synergistic long-lasting blood pressure control
Providing a pharmaceutical composition comprising a vasoactive intestinal peptide (VIP) having a binding preference for VPAC2, where the VIP comprises the amino acid sequence of SEQ ID NO: 13 with the N-terminal His at position 2 and an N-terminal methionine and an elastin-like peptide (ELP) at the C-terminus, wherein the ELP comprises at least 90 repeats of VPGXG (SEQ ID NO: 3), the VIP demonstrates an extended half-life in circulation, and the co-administration of the VIP and the anti-hypertensive drug produces a synergistic increase in long-lasting blood pressure control compared to administering VIP alone, with the anti-hypertensive drug selected from an α1 receptor antagonist, an ACE inhibitor, and a calcium channel blocker.
Across both independent claims, the inventive concept is the VPAC2-preferential VIP construct with SEQ ID NO: 13 features and a C-terminal ELP comprising at least 90 VPGXG repeats, exhibiting extended half-life in circulation, combined with one selected standard anti-hypertensive drug class member to achieve a synergistic increase in long-lasting blood pressure control versus VIP alone.
Stated Advantages
Extended half-life in circulation for the VIP.
Synergistic increase in long-lasting blood pressure control compared to administering VIP alone.
Documented Applications
Treating hypertension in a patient by administering a VPAC2-preferential VIP construct together with at least one anti-hypertensive drug selected from an α1 receptor antagonist, an ACE inhibitor, and a calcium channel blocker.
Providing a pharmaceutical composition comprising the VPAC2-preferential VIP construct together with at least one selected anti-hypertensive drug to achieve synergistic, long-lasting blood pressure control.
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