Synthetic ion channels
Provided herein are self-assembling compounds that can form ion channels in lipid bilayers or cell membranes and ion-channel-forming compositions comprising the self-assembling compounds. Also provided are methods of making and using the ion channels formed from a plurality of molecules of the self-assembling compounds. Further, provided are methods of treating or preventing conditions and diseases that are related to the dysfunction of ion channels, including chloride channels.
1. A self-assembling compound for the formation of ion channels in lipid bilayers or cell membranes having formula (I):
or a salt, solvate, polymorph or stereoisomer thereof,
wherein X is an unsubstituted or substituted hydrocarbyl or heterocyclyl;
n is an integer from 1 to 6;
Y is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent linking group formed by removing one, two, three, four, five and six hydrogen atoms respectively from an unsubstituted or substituted hydrocarbon or carbocycle; and
H DA is a divalent group having formula (II):
wherein each of Z 1 and Z 2 is independently O, S or NR 1 ;
each of A, B 1 , B 2 , B 3 and D is independently a bond, O, S, NR 2 or a substituted or unsubstituted C 1-10 alkylene; and
k is an integer from 1 to 20, where each of R 1 and R 2 is independently H, acyl, hydrocarbyl, carbocyclyl or heterocyclyl and at least one of B 1 and B 2 is NH.
2. The self-assembling compound of claim 1 , wherein Y is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent linking group formed by removing one, two, three, four, five and six hydrogen atoms respectively from an unsubstituted or substituted hydrocarbon or carbocycle.
3. The self-assembling compound of claim 1 , wherein at least one of Z 1 or Z 2 is S or NR 1 .
4. The self-assembling compound of claim 1 , wherein at least one of A, B 2 , and D is O or S.
5. The self-assembling compound of claim 1 , wherein each of A and D is a bond.
6. The self-assembling compound of claim 1 , wherein each of B 1 , B 2 , and B 3 is independently NH.
7. The self-assembling compound of claim 1 , wherein X is hydrocarbyl or substituted hydrocarbyl.
8. The self-assembling compound of claim 1 , wherein the compound is selected from
9. A self-assembling compound for the formation of ion channels in lipid bilayers or cell membranes having formula (I):
or a salt, solvate, polymorph or stereoisomer thereof,
wherein X is an unsubstituted or substituted hydrocarbyl or heterocyclyl;
n is an integer from 1 to 6;
Y is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent linking group formed by removing one, two, three, four, five and six hydrogen atoms respectively from an unsubstituted or substituted hydrocarbon or carbocycle; and
H DA is a divalent group having formula (X):
wherein each of Z 1 and Z 2 is independently O, S or NR 1 ;
each of A, B 1 , B 2 , B 3 , C, and D is independently a bond, O, S, NR 2 or a substituted or unsubstituted C 1-10 alkylene; and
k is an integer from 1 to 20, where each of R 1 and R 2 is independently H, acyl, hydrocarbyl, carbocyclyl or heterocyclyl and at least one of B 1 and B 2 is NH.
10. The self-assembling compound of claim 9 , wherein at least one of Z 1 or Z 2 is S or NR 1 .
11. The self-assembling compound of claim 9 , wherein at least one of A, B 2 , C, and D is O or S.
12. The self-assembling compound of claim 9 , wherein each of B 1 , B 2 , and B 3 is independently NH.
13. A composition, comprising a cell membrane and a plurality of molecules of the self-assembling compound of claim 9 .
14. The composition of claim 13 , wherein the cell membrane comprises a lipid bilayer.
15. The composition of claim 14 , wherein the plurality of molecules self-assemble to form an anion channel across the thickness of the lipid bilayer.
16. The composition of claim 15 , wherein the anion channel is a fluoride, chloride, bromide, iodide, nitrate, nitrite, sulfate, bisulfate, carbonate, bicarbonate, phosphate, hydrogen phosphate, dihydrogen phosphate or acetate channel.
17. The composition of claim 16 , wherein the anion channel is a chloride channel.
18. A method of forming a synthetic anion channel in a cell membrane, the method comprising the step of combining the cell membrane with a plurality of molecules of the self-assembling compound of claim 9 .
19. The method of claim 18 , wherein the cell membrane comprises a lipid bilayer.
20. A method of modulating the flow of ions through a cell membrane, the method comprising the steps of forming an anion channel in the membrane from a plurality of molecules of the self-assembling compound of claim 9 ; and imposing an ion gradient or a membrane potential across the cell membrane.
21. The method of claim 20 , wherein the cell membrane comprises a lipid bilayer.
22. A method of making a synthetic ion channel in a cell membrane comprising the steps of:
(a) providing a plurality of molecules of the self-assembling compound of claim 9 ; and
(b) forming molecular columns in the transverse direction of the membrane and between any two adjacent molecular columns by the self-assembling of the molecules through intermolecular hydrogen bonds in the lateral direction of the membrane.
23. The method of claim 22 , wherein the cell membrane comprises a lipid bilayer.
24. A method of treating, managing or preventing a disease that is related to the dysfunction of chloride channel, the method comprising administering a plurality of molecules of a self-assembling compound of claim 9 or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof.
25. The method of claim 24 , wherein the disease is cystic fibrosis, Bartter's syndrome, Dent's disease, inherited kidney stone disease, myotonia congenita, Becker syndrome, epilepsy, vitelliform macular dystrophy, hyperekplexia, juvenile myoclonus epilepsy or osteopetrose.
26. The method of claim 24 , wherein the self-assembling compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is inserted into the lipid bilayer of a cell of a mammal.
27. The method of claim 24 , wherein the mammal is a human.
28. A pharmaceutical composition, comprising the self-assembling compound of claim 9 or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, and a pharmaceutically acceptable carrier.
29. The pharmaceutical composition of claim 28 , further comprising at least an ingredient selected from the group consisting of excipients, moisturizers, diluents, metal stearates and combinations thereof.
30. The pharmaceutical composition of claim 28 , which is in a single unit dosage form.
31. The pharmaceutical composition of claim 28 , which is in a single unit dosage form suitable for inserting into the lipid bilayer of a mammalian cell.
32. An ion channel comprising a plurality of molecules of the self-assembling compound of claim 9 , wherein the ion channel is in a cell membrane.
33. The ion channel of claim 32 , wherein the ion channel is an anion channel.
34. The ion channel of claim 32 , wherein the cell membrane comprises a lipid bilayer.