NANOMATERIALS COMPRISING TRIOLS
The present disclosure describes compositions, preparations, nanoparticles (such as lipid nanoparticles), and/or nanomaterials and methods of their use.
1 . A compound of Formula VII-A or Formula VII-B:
or a pharmaceutically acceptable salt thereof, wherein:
each L 2 and L 2′ is independently an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
L 3 is —O—, —OC(O)—, or —OC(O)O—;
R 1 is optionally substituted C 1-20 aliphatic,
L CyA is a covalent bond or an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
Cy A is an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
L Ra is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
each R a and R 1′ is independently optionally substituted C 1-20 aliphatic;
Y 2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-6 hydrocarbon chain;
Y 3 is optionally substituted C 1-20 aliphatic;
X z is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR—;
X 3 is hydrogen or an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R is independently hydrogen or optionally substituted C 1-6 aliphatic.
2 . A lipid nanoparticle (LNP) preparation comprising:
an ionizable lipid, or a pharmaceutically acceptable salt thereof, according to claim 1 ;
a therapeutic and/or prophylactic agent;
a phospholipid;
a cholesterol; and
a conjugate-linker lipid.
3 . A method of base editing a genome of a cell, the method comprising contacting the cell with the LNP preparation of claim 2 to the subject, wherein the therapeutic and/or prophylactic agent comprises mRNA encoding a base editor and a chemically modified sgRNA.
4 . A method of producing a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the LNP preparation of claim 2 , wherein the therapeutic and/or prophylactic agent is or comprises an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.
5 . A compound of Formula VII-A or Formula VII-B:
or a pharmaceutically acceptable salt thereof, wherein:
each L 2 and L 2′ is independently an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
L 3 is a covalent bond;
R 1 is optionally substituted C 1-20 aliphatic,
L CyA is a covalent bond or an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
Cy A is an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
L Ra is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
each R a and R 1′ is independently optionally substituted C 1-20 aliphatic;
Y 2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-6 hydrocarbon chain;
Y 3 is optionally substituted C 1-20 aliphatic;
X 1 is a covalent bond, —O—, or —NR—;
X 2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR—;
X 3 is hydrogen or an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R is independently hydrogen or optionally substituted C 1-6 aliphatic.
6 . A lipid nanoparticle (LNP) preparation comprising:
an ionizable lipid, or a pharmaceutically acceptable salt thereof, according to claim 5 ;
a therapeutic and/or prophylactic agent;
a phospholipid;
a cholesterol; and
a conjugate-linker lipid.
7 . A method of base editing a genome of a cell, the method comprising contacting the cell with the LNP preparation of claim 6 to the subject, wherein the therapeutic and/or prophylactic agent comprises mRNA encoding a base editor and a chemically modified sgRNA.
8 . A method of producing a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the LNP preparation of claim 6 , wherein the therapeutic and/or prophylactic agent is or comprises an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.
9 . A compound of Formula VIII-A or Formula VIII-B:
or a pharmaceutically acceptable salt thereof, wherein:
each L 2 and L 2′ is independently an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
L 3 is a covalent bond, —O—, —C(O)O—, —OC(O)—, or —OC(O)O—;
R 1 is optionally substituted C 1-20 aliphatic,
L CyA is a covalent bond or an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
Cy A is an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
L Ra is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
each R a and R 1′ is independently optionally substituted C 1-20 aliphatic;
Y 2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-6 hydrocarbon chain;
Y 3 is optionally substituted C 1-20 aliphatic;
X 2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR—;
X 3 is hydrogen or an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R is independently hydrogen or optionally substituted C 1-6 aliphatic.
10 . A lipid nanoparticle (LNP) preparation comprising:
an ionizable lipid, or a pharmaceutically acceptable salt thereof, according to claim 9 ;
a therapeutic and/or prophylactic agent;
a phospholipid;
a cholesterol; and
a conjugate-linker lipid.
11 . A method of base editing a genome of a cell, the method comprising contacting the cell with the LNP preparation of claim 10 to the subject, wherein the therapeutic and/or prophylactic agent comprises mRNA encoding a base editor and a chemically modified sgRNA.
12 . A method of producing a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the LNP preparation of claim 10 , wherein the therapeutic and/or prophylactic agent is or comprises an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.
13 . A compound of Formula IX-A or Formula IX-B:
or a pharmaceutically acceptable salt thereof, wherein:
each L 2 and L 2′ is independently an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
R 1 is optionally substituted C 1-20 aliphatic,
L CyA is a covalent bond or an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
Cy A is an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
L Ra is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
each R a and R 1′ is independently optionally substituted C 1-20 aliphatic;
Y 2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-6 hydrocarbon chain;
Y 3 is optionally substituted C 1-20 aliphatic;
X 2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR—;
X 3 is hydrogen or an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R is independently hydrogen or optionally substituted C 1-6 aliphatic.
14 . A lipid nanoparticle (L-NP) preparation comprising:
an ionizable lipid, or a pharmaceutically acceptable salt thereof, according to claim 13 ;
a therapeutic and/or prophylactic agent;
a phospholipid;
a cholesterol; and
a conjugate-linker lipid.
15 . A method of base editing a genome of a cell, the method comprising contacting the cell with the LNP preparation of claim 14 to the subject, wherein the therapeutic and/or prophylactic agent comprises mRNA encoding a base editor and a chemically modified sgRNA.
16 . A method of producing a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the LNP preparation of claim 14 , wherein the therapeutic and/or prophylactic agent is or comprises an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.
17 . A compound of Formula X-A or Formula X-B:
or a pharmaceutically acceptable salt thereof, wherein:
each L 2 and L 2′ is independently an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
R 1 is optionally substituted C 1-20 aliphatic,
L CyA is a covalent bond or an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
Cy A is an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;
L Ra is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain;
each R a and R 1′ is independently optionally substituted C 1-20 aliphatic;
Y 2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-6 hydrocarbon chain;
Y 3 is optionally substituted C 1-20 aliphatic;
X 2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1-12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR—;
X 3 is hydrogen or an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R is independently hydrogen or optionally substituted C 1-6 aliphatic.
18 . A lipid nanoparticle (LNP) preparation comprising:
an ionizable lipid, or a pharmaceutically acceptable sale thereof, according to claim 17 ;
a therapeutic and/or prophylactic agent;
a phospholipid;
a cholesterol; and
a conjugate-linker lipid.
19 . A method of base editing a genome of a cell, the method comprising contacting the cell with the LNP preparation of claim 18 to the subject, wherein the therapeutic and/or prophylactic agent comprises mRNA encoding a base editor and a chemically modified sgRNA.
20 . A method of producing a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the LNP preparation of claim 18 , wherein the therapeutic and/or prophylactic agent is or comprises an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.