CELL PENETRATING PEPTIDES AND METHODS OF MAKING AND USING THEREOF

• US 20170190743A1
• Filed: 05/21/2015
• Published: 07/06/2017
• Est. Priority Date: 05/21/2014
• Status: Active Grant

• Current Assignee: Entrada Therapeutics Inc., Ohio State Innovation Foundation (Ohio State University)
• Original Assignee: CycloPorters, Inc.
• Inventors: PEI, Dehua, QIAN, Ziqing
• Granted Patent: US 10,626,147 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/465 acting on ester bonds (3.1), e.g. lipases, ribonucleases
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 49/0039 Coumarin dyes
• CPC Class Codes: A61K 49/0041 Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal in vivo G01N
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0047 Green fluorescent protein [GFP]
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links
• CPC Class Codes: C12Y 301/03048 Protein-tyrosine-phosphatase (3.1.3.48)

Abstract

Disclosed herein are compounds having activity as cell penetrating peptides. In some examples, the compounds can comprise a cell penetrating peptide moiety and a cargo moiety. The cargo moiety can comprise one or more detectable moieties, one or more therapeutic moieties, one or more targeting moieties, or any combination thereof. In some examples, the cell penetrating peptide moiety is cyclic. In some examples, the cell penetrating peptide moiety and cargo moiety together are cyclic. In some examples, the cell penetrating peptide moiety is cyclic and the cargo moiety is appended to the cyclic cell penetrating peptide moiety structure. In some examples, the cargo moiety is cyclic and the cell penetrating peptide moiety is cyclic, and together they form a fused bicyclic system.

Claims

1-61. -61. (canceled)

62. A cyclic peptide comprising formula Ia:

63. The cyclic peptide according to claim 62, wherein:

m and n are each 0;

p is 1; and

AA⁹ is L-glutamine.

64. The cyclic peptide according to claim 62, wherein:

m is 0;

n and p are each 1;

AA⁸ is L-arginine; and

AA⁹ is L-glutamine.

65. The cyclic peptide according to claim 62, wherein:

m is 0;

n and p are each 1;

AA⁸ is L-glutamine; and

AA⁹ is L-phenylalanine.

66. The cyclic peptide according to claim 62, wherein the cyclic peptide has a cellular uptake efficiency that is at least about five-fold higher than the cellular uptake efficiency of a peptide having an otherwise identical amino acid sequence in which the amino acids are all L-amino acids.

67. The cyclic peptide according to claim 62, further comprising a cargo moiety, wherein the cargo moiety comprises a detectable moiety, a therapeutic moiety, a targeting moiety, or a combination thereof.

68. A cyclic peptide comprising formula IIa, IIb, or IIc:

69. The cyclic peptide according to claim 68, wherein:

m and n are each 0;

p is 1; and

AA⁹ is L-glutamine.

70. The cyclic peptide according to claim 68, wherein:

m is 0;

n and p are each 1;

AA⁸ is L-arginine; and

AA⁹ is L-glutamine.

71. The cyclic peptide according to claim 68, wherein:

m is 0;

n and p are each 1;

AA⁸ is L-glutamine; and

AA⁹ is L-phenylalanine.

72. The cyclic peptide according to claim 68, wherein the cyclic peptide has a cellular uptake efficiency that is at least about five-fold higher than the cellular update efficiency of a peptide having an otherwise identical amino acid sequence in which the amino acids are all L-amino acids.

73. A method for delivery a therapeutic agent to cytoplasm of a cell, comprising administering at least one cyclic peptide comprising formula IIa, IIb, or IIc to a cell:

74. The method of claim 73, wherein:

AA¹ is L-phenylalanine;

AA² is L-naphthylalanine;

AA³ is L-arginine;

AA⁴ is L-arginine;

AA⁵ is L-arginine;

AA⁶ is L-arginine;

m and n are each 0;

p is 1; and

AA⁹ is L-glutamine.

75. The method of claim 73, wherein:

AA¹ is D-phenylalanine;

AA² is L-naphthylalanine;

AA³ is L-arginine;

AA⁴ is D-arginine;

AA⁵ is L-arginine; and

AA⁶ is D-arginine.

76. The method of claim 75, wherein:

m and n are each 0;

p is 1; and

AA⁹ is L-glutamine.

77. The method of claim 75, wherein:

m is 0;

n and p are each 1;

AA⁸ is L-arginine; and

AA⁹ is L-glutamine.

78. The method of claim 75, wherein:

m is 0;

n and p are each 1;

AA⁸ is L-glutamine; and

AA⁹ is L-phenylalanine.

79. The method of claim 73, wherein the therapeutic agent is an inhibitor against Ras, PTP1B, Pin1, Grb2, SH2, or combinations thereof.

80. The method of claim 73, wherein the cyclic, cell-penetrating peptide further comprises a detectable moiety, a targeting moiety, or a combination thereof.