Cardiac-specific targeting-peptide (CTP), compositions, and uses thereof

Pending Publication Date: 2021-07-08
UNIVERSITY OF PITTSBURGH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]In one aspect, a peptide comprising a CTP of SEQ ID NO: 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 28, 29, or 34 is linked to a moiety having antiarrhythmic properties. Moieties with antiarrhythmic properties include compounds that can be grouped into 4 main classes of antiarrhythmics (classes I, II, III, and IV) under the Vaughan Williams classification scheme. The Vaughan Williams classification scheme categorizes antiarrhythmics according to their dominant cellular electrophysiologic effect and mechanism of action.
[0010]Class I compounds include sodium channel blockers (membrane-stabilizing drugs) that can block fast sodium channels, slowing conduction in fast-channel tissues (for example, in working atrial and ventricular myocytes, and in the His-Purkinje system). Class I compounds can be subdivided into subclasses a, b, and c, with subclass a compounds (for example, anticholinergics such as quinidine, procainamide, and disopyramide) having moderate effects, subclass b compounds (for example, lidocaine and lidocaine analogs, including tocainide and mexiletine) having weak effects, and subclass c compounds (for example, fl

Problems solved by technology

Ventricular fibrillation (VFib) is a serious cardiac disturbance that is a life-threatening rhythm and a common cause of sudden cardiac death.
One of the most effective pharmaceutical therapies for AFib and VFib, amiodarone, has significant sys

Method used

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  • Cardiac-specific targeting-peptide (CTP), compositions, and uses thereof
  • Cardiac-specific targeting-peptide (CTP), compositions, and uses thereof
  • Cardiac-specific targeting-peptide (CTP), compositions, and uses thereof

Examples

Experimental program
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Effect test

example 1

can Analysis of the Cardiac-Specific Targeting Peptide

[0191]This example describes the design and testing of cardiac-specific targeting peptide variants to determine the contribution of each amino acid residue to transduction activity.

[0192]Previous studies had identified a synthetic 12-amino acid peptide (APWHLSSQYSRT; SEQ ID NO: 1) capable of transducing cardiomyocytes. Alanine scanning analysis of the APWHLSSQYSRT (SEQ ID NO: 1) sequence was performed to assess the importance and relative contribution of each amino acid residue to the cell penetrating ability.

[0193]Variants of SEQ ID NO: 1 in which every amino acid was systematically mutated to alanine were synthesized in the University of Pittsburgh Peptide Synthesis Facility. Each variant was conjugated to the Cyanine5.5 fluorescent dye (Cy5.5). The rat cardiomyocyte cell line H9C2 (ATCC, catalogue #: CRL-1446) was incubated for 30 minutes at 37° C. with Dimethyl sulfoxide (DMSO) as a control, or the alanine peptide variants. C...

example 2

Transduction and Viability Studies of N- and C-Terminal Cardiac-Specific Targeting Peptides

[0196]The results described in Example 1 suggested that the cell penetrating ability of the cardiac-specific targeting peptide (APWHLSSQYSRT; SEQ ID NO: 1) resides in the 6 C-terminal amino acid residues. To evaluate this further, variants of SEQ ID NO: 1, including linear and cyclized 6-amino acid N- and C-terminal variants, were synthesized in the University of Pittsburgh Peptide Synthesis Facility. Each variant was conjugated to Cy5.5.

[0197]Solid-phase peptide synthesis were used to synthesize the full-length form (NH2-APWHLSSQYSRT-COOH (SEQ ID NO: 1)), as well as an N-terminus 6 amino acid called CTP-A (NH2-APWHLS-COOH (SEQ ID NO: 24)), or as CTP6aa (NH2-SQYSRT-COOH (SEQ ID NO: 5)) peptides. Full length and CTP6aa were also synthesized in a cyclic forms. A random, linear, 12-amino acid long peptide (RAN: NH2-STLMKFCYVEQN-COOH (SEQ ID NO: 26)) was also synthesized to serve as control. All p...

example 3

of Rhodamine Cargo to Cardiomyocytes Via Conjugation to the C-Terminus of the Cardiac-Specific Targeting Peptide

[0200]This example describes the use of the cardiac-specific targeting peptide via conjugation at the C-terminus to deliver a rhodamine cargo to the intracellular compartments of cardiomyocytes.

[0201]The cardiac-specific targeting peptide was synthesized in the University of Pittsburgh Peptide Synthesis Facility and labeled at the N-terminus with carboxyfluorescein (green), and with rhodamine (red) at the C-terminus through an ester linkage. Beating cardiomyocytes derived from human induced pluripotent stem cells (iPSC) were then incubated with the dual labeled peptide for 30 minutes at 37° C., washed 3× with PBS and immediately thereafter, live cell imaging was performed using confocal microscopy.

[0202]As shown in FIG. 3C, the dual labeled peptide successfully entered the beating human iPSC derived cardiomyocytes, and also that ester-linkage of a cargo to the C-terminus o...

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Abstract

Disclosed is a synthetic, non-naturally occurring 12-amino acid peptide, Cardiac Targeting Peptide, belonging to the larger class of cell penetrating peptides, for delivery of both diagnostic and potentially therapeutic agents to the heart. Also disclosed are subsequent generations of this Cardiac Targeting Peptide with improved, higher efficiency of cardiac uptake for CTP-mediated delivery of antiarrhythmics subjects for treating Atrial fibrillation or Ventricular fibrillation, CTP-mediated delivery of neuregulin-1β for treating systolic heart failure (SHF), and Szeto-Schiller peptides for treatment of diastolic congestive heart failure, among other applications.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 675,307, filed May 23, 2018; U.S. Provisional Patent Application No. 62 / 778,033, filed Dec. 11, 2018; and U.S. Provisional Patent Application No. 62 / 811,077, filed Feb. 27, 2019; the disclosure of each of which is hereby incorporated by reference in its entirety for all purposes.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 21, 2019, is named UPB-013WO_ST25.txt and is 11,293 bytes in size.FIELD OF THE INVENTION[0003]The invention relates generally to cardiac-specific targeting peptides (CTP)-mediated delivery of moieties having antiarrhythmic properties for treating Atrial fibrillation or Ventricular fibrillation, and CTP-mediated delivery of neuregulin-1β for treating sys...

Claims

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Application Information

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IPC IPC(8): C07K7/08
CPCC07K7/08A61K38/00C07K7/06C07K2319/00G01N33/582C07K2319/10C07K2319/60A61K9/0019A61P9/06A61P39/06C12Y114/99003
Inventor ZAHID, MALIHA
Owner UNIVERSITY OF PITTSBURGH
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