Engineered peptide and peptide mimetic compositions and methods
The present invention relates to Mitochondrial Fission Factor (MFF)-derived peptides or peptide mimetics and to methods of making MFF-derived peptides or peptide mimetics. Also provided are methods of treating a disease in a subject in need thereof, comprising administering to the subject an effective amount of a MFF-derived peptide or peptide mimetic.
1 . A peptide having MFF-VDAC1 disrupting activity, comprising the sequence of:
SEQ ID NO: 8, wherein the peptide is 30 amino acids in length;
SEQ ID NO: 11, wherein the peptide is 27 amino acids in length;
SEQ ID NO: 12, wherein the peptide is 24 amino acids in length;
SEQ ID NO: 16, wherein the peptide is 27 amino acids in length; or
SEQ ID NO: 21, wherein the peptide is 21 amino acids in length.
2 . The peptide of claim 1 , wherein the peptide is conjugated to a cell-penetrating amino acid sequence.
3 . The peptide of claim 2 , wherein the cell-penetrating amino acid sequence is selected from the group consisting of an HIV-Tat cell-penetrating sequence, penetratin (also known as antennapedia), cR10 and Pep-1.
4 . The peptide of claim 2 , wherein the cell-penetrating amino acid sequence comprises SEQ ID NO: 24.
5 . A polynucleotide encoding the peptide of claim 1 .
6 . A pharmaceutical composition comprising the polynucleotide of claim 5 and a pharmaceutically acceptable carrier, diluent or excipient.
7 . A pharmaceutical composition comprising at least one of the peptides of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.
8 . A method of treating VDAC1 expressing cancer in a subject in need thereof, comprising administering to the subject an effective amount of the peptide of claim 1 .
9 . The method of claim 8 , wherein the cancer is prostate cancer, glioblastoma, breast cancer, breast adenocarcinoma, lung cancer, non-small cell lung cancer, melanoma, ovarian cancer, hematological B-cell cancer, hematological T-cell cancer, metastatic cancer, treatment-resistant tumor or myc+ cancer.
10 . The method of claim 8 , further comprising administering a second agent to the subject.
11 . The method of claim 10 , wherein the second agent is a molecularly targeted therapy, a vaccine, a chemotherapeutic agent, radiation, or combinations thereof.
12 . A method of disrupting the MFF-VDAC1 complex in a subject in need thereof, comprising administering to the subject an effective amount of the peptide of claim 1 .
13 . A kit comprising the pharmaceutical composition of claim 6 and a delivery agent.
14 . The kit of claim 13 , wherein the delivery agent is for oral, intranasal, transbuccal, transdermal, intraperitoneal, intramuscular, intravenous, or other injectable form of delivery.
15 . A peptide mimetic, wherein the peptide mimetic is a retro-inverso D-enantiomer of the peptide of claim 1 .
16 . The peptide mimetic of claim 15 , wherein the peptide-comprises the sequence of SEQ ID NO: 21.
17 . The peptide mimetic of claim 15 , wherein the peptide mimetic is conjugated to a cell-penetrating amino acid sequence.
18 . The peptide mimetic of claim 17 , wherein the cell-penetrating amino acid sequence is an HIV-Tat cell-penetrating sequence, penetratin, cR10 or Pep-1.
19 . The peptide mimetic of claim 18 , wherein the cell-penetrating amino acid sequence is SEQ ID NO: 24.
20 . A pharmaceutical composition comprising the peptide mimetic of claim 15 and a pharmaceutically acceptable carrier, diluent or excipient.
21 . A method of treating VDAC1 expressing cancer in a subject in need thereof, comprising administering to the subject an effective amount of the peptide of claim 15 .
22 . The method of claim 21 , wherein the cancer is prostate cancer, glioblastoma, breast cancer, breast adenocarcinoma, lung cancer, non-small cell lung cancer, melanoma, ovarian cancer, hematological B-cell cancer, hematological T-cell cancer, metastatic cancer, treatment-resistant tumor or myc+ cancer.
23 . The method of claim 21 , further comprising administering a second agent to the subject.
24 . The method of claim 23 , wherein the second agent is a molecularly targeted therapy, a vaccine, a chemotherapeutic agent, radiation, or combinations thereof.
25 . A method of disrupting the MFF-VDAC1 complex in a subject in need thereof, comprising administering to the subject an effective amount of the peptide of claim 15 .
26 . A kit comprising the pharmaceutical composition of claim 20 and a delivery agent.
27 . The kit of claim 26 , wherein the delivery agent is for oral, intranasal, transbuccal, transdermal, intraperitoneal, intramuscular, intravenous, or other injectable form of delivery.
28 . A peptide comprising a first amino acid sequence and a second amino acid sequence, wherein the first amino acid sequence is an MFF derived peptide of no more than 30 amino acids in length, having the sequence set forth in any one of SEQ ID NOs: 1-23; and wherein the second amino acid sequence is a cell-penetrating amino acid sequence.
29 . The peptide of claim 28 , wherein the first amino acid sequence is the sequence set forth in any one of SEQ ID NOs: 8, 11, 12, 16, and 21.
30 . The peptide of claim 29 , wherein the cell-penetrating amino acid sequence is selected from the group consisting of an HIV-Tat cell-penetrating sequence, penetratin (also known as antennapedia), cR10 and Pep-1.
31 . The peptide of claim 29 , wherein the cell-penetrating amino acid sequence comprises SEQ ID NO: 24.