Inhibitors of mitochondrial fission and methods of use thereof
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 binding of dynamin-1-related protein (Drp1) GTPase activity, 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 peptide consisting of (i) YGRKKRRQRRR (SEQ ID NO: 31), (ii) GG and (iii) DLLPRGS (SEQ ID NO: 12) attached in the order (i), (ii), and (iii) from amino terminus to carboxyl terminus, or a pharmaceutically acceptable salt thereof, wherein the carboxyl terminus of the peptide or pharmaceutically acceptable salt thereof is optionally chemically modified by amidation.
2. The peptide of claim 1 , wherein the pharmaceutically acceptable salt thereof is an acid addition salt, and wherein the acid addition salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphorate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartarate, citrate, benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, or salicylate.
3. The peptide of claim 1 , wherein the pharmaceutically acceptable salt thereof is a base addition salt, and wherein the base addition salt is formed by adding sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, ammonia, ethylenediamine, arginine, or piperazine.
4. The peptide of claim 2 , wherein the acid addition salt is acetate.
5. A pharmaceutical composition comprising the peptide of claim 1 and a pharmaceutically acceptable excipient.
6. A peptide comprising (i) YGRKKRRQRRR (SEQ ID NO: 31), (ii) GG, and (iii) DLLPRGS (SEQ ID NO: 12) attached in the order (i), (ii), and (iii) from amino terminus to carboxyl terminus, or a pharmaceutically acceptable salt thereof.
7. The peptide of claim 6 , wherein the carboxyl terminus of the peptide is chemically modified by amidation.
8. The peptide of claim 6 , wherein the pharmaceutically acceptable salt thereof is an acid addition salt, and wherein the acid addition salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphorate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartarate, citrate, benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, or salicylate.
9. The peptide of claim 6 , wherein the pharmaceutically acceptable salt thereof is a base addition salt, and wherein the base addition salt is formed by adding sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, ammonia, ethylenediamine, arginine, or piperazine.
10. The peptide of claim 8 , wherein the acid addition salt is acetate.
11. A pharmaceutical composition comprising the peptide of claim 6 and a pharmaceutically acceptable excipient.