Inhibitors of mitochondrial fission and methods of use thereof
View Patent ↗The present disclosure provides peptides and constructs that inhibit mitochondrial fission, and compositions comprising the peptides or constructs. The present disclosure provides methods of reducing abnormal mitochondrial fission in a cell. Also provided are methods for designing and validating mitochondrial fission inhibitor constructs and peptides, including but not limited to, evaluating the effects of the constructs and peptides on dynamin 1-like protein (Drp1) guanosine triphosphate phosphatase (GTPase) activity, binding of Drp1 to mitochondrial fission 1 protein (Fis1), reduction of mitochondrial damage, reduction in cell death, inhibition of mitochondrial fragmentation in a cell under pathological conditions, and reduced loss of neurites in primary dopaminergic neurons in a Parkinsonism cell culture.
1. A mitochondrial fission inhibitor peptide consisting of 7, 8 or 9 amino acids, wherein the inhibitor peptide has at least 80% amino acid sequence identity to SEQ ID NO:13, and wherein the inhibitor peptide inhibits a guanosine triphosphate phosphatase (GTPase) activity of the Dynamin 1-like protein (Drp1) (SEQ ID NO:1).
2. A mitochondrial fission inhibitor linear peptide construct comprising:
a) the fission inhibitor peptide according to claim 1 ;
b) an optional linker; and
c) a carrier peptide selected from the group consisting of SEQ ID NOs:31-45;
wherein the mitochondrial fission inhibitor linear peptide construct is no more than 62 amino acids in length.
3. The inhibitor construct of claim 2 , wherein the carrier peptide is SEQ ID NO:32 or SEQ ID NO:33.
4. The inhibitor linear peptide construct of claim 2 , comprising the linker, wherein the linker is positioned between the fission inhibitor peptide and the carrier peptide, wherein the linker is selected from the group consisting of G, GG, GGG and GGGG (SEQ ID NO:62).
5. The inhibitor linear peptide construct of claim 2 , wherein the fission inhibitor peptide consists of SEQ ID NO:12 or SEQ ID NO:13.
6. The inhibitor linear peptide construct of claim 4 , consisting of SEQ ID NO:19 or SEQ ID NO:20.
7. A pharmaceutical composition comprising the mitochondrial fission inhibitor peptide of claim 1 and a pharmaceutically acceptable excipient.
8. A pharmaceutical composition comprising the inhibitor linear peptide construct of claim 2 and a pharmaceutically acceptable excipient.