IP Library › Granted Patent US 12,655,436
Granted Patent B2
US 12,655,436 · App. 17/881,471 · Granted Jun 16, 2026

Import of unnatural or modified nucleoside triphosphates into cells via nucleic acid triphosphate transporters

Inventors: Floyd E. Romesberg (La Jolla, CA); Denis A. Malyshev (La Jolla, CA)
Assignee: The Scripps Research Institute
C12N15/70C07K14/295C07K14/405C12N15/8243C12P19/34
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Quick Facts
Patent No.
US 12,655,436
App. No.
17/881,471
Granted
Jun 16, 2026
Kind
B2
Abstract

A recombinantly expressed nucleotide triphosphate transporter efficiently imports the triphosphates of unnatural nucleotides into cells, and the endogenous cellular machinery incorporates those nucleotides into cellular nucleic acids. UBPs can therefore form within the cell's nucleic acids. Moreover, neither the presence of the unnatural triphosphates nor the replication of the UBP represents a significant growth burden. The UBP is not efficiently excised by nucleic acid repair pathways, and therefore can be retained as long as the unnatural triphosphates are available in the growth medium. Thus, the resulting cell is the first organism to stably propagate an expanded genetic alphabet.

Claims (52)

1 . An isolated prokaryotic cell comprising:

(a) a heterologous nucleoside triphosphate transporter comprising an amino acid sequence that is at least about 85% identical to SEQ ID NO: 1; and

(b) a first unnatural nucleotide comprising a base selected from:

wherein the heterologous nucleoside triphosphate transporter is capable of transporting triphosphates of the first unnatural nucleotide into the cell.

2 . The isolated cell of claim 1 , wherein the heterologous nucleoside triphosphate transporter comprises an amino acid sequence that is at least about 90% identical to SEQ ID NO: 1.

3 . The isolated cell of claim 1 , further comprising a second unnatural nucleotide comprising a base selected from:

4 . The isolated cell of claim 3 , wherein the first unnatural nucleotide and the second unnatural nucleotide each independently comprise a base selected from:

5 . The isolated cell of claim 4 , wherein the first unnatural nucleotide and the second unnatural nucleotide each independently comprise a base selected from:

6 . The isolated cell of claim 5 , wherein the first unnatural nucleotide and the second unnatural nucleotide each independently comprise a base selected from

7 . The isolated cell of claim 3 , wherein:

(a) the first unnatural nucleotide comprises a base selected from

and;

(b) the second unnatural nucleotide comprises a base selected from

8 . The isolated cell of claim 7 , wherein the second unnatural nucleotide comprises a base selected from

9 . The isolated cell of claim 8 , wherein the second unnatural nucleotide comprises a base selected from

10 . The isolated cell of claim 9 , wherein:

(a) the first unnatural nucleotide comprises a base which is

and

(b) the second unnatural nucleotide comprises a base selected from

11 . The isolated cell of claim 9 , wherein the second unnatural nucleotide comprises a base which is

12 . An isolated prokaryotic cell comprising:

(a) a heterologous nucleoside triphosphate transporter comprising an amino acid sequence that is at least about 85% identical to SEQ ID NO: 1; and

(b) a first unnatural nucleotide,

wherein the heterologous nucleoside triphosphate transporter is capable of transporting triphosphates of the first unnatural nucleotide into the cell.

13 . The isolated cell of claim 12 , wherein the first unnatural nucleotide comprises a base or is selected from: 2-aminoadenin-9-yl, 2-aminoadenine, 2-F-adenine, 2-thiouracil, 2-thio-thymine, 2-thiocytosine, 2-propyl and alkyl derivatives of adenine and guanine, 2-amino-adenine, 2-amino-propyl-adenine, 2-aminopyridine, 2-pyridone, 2′-deoxyuridine, 2-amino-2′-deoxyadenosine 3-deazaguanine, 3-deazaadenine, 4-thio-uracil, 4-thio-thymine, uracil-5-yl, hypoxanthin-9-yl (I), 5-methyl-cytosine, 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 5-bromo, and 5-trifiuoromethyl uracils and cytosines; 5-halouracil, 5-halocytosine, 5-propynyl-uracil, 5-propynyl cytosine, 5-uracil, 5-substituted, 5-halo, 5-substituted pyrimidines, 5-hydroxycytosine, 5-bromocytosine, 5-bromouracil, 5-chlorocytosine, chlorinated cytosine, cyclocytosine, cytosine arabinoside, 5-fluorocytosine, fluoropyrimidine, fluorouracil, 5,6-dihydrocytosine, 5-iodocytosine, hydroxyurea, iodouracil, 5-nitrocytosine, 5-bromouracil, 5-chlorouracil, 5-fluorouracil, and 5-iodouracil, 6-alkyl derivatives of adenine and guanine, 6-azapyrimidines, 6-azo-uracil, 6-azo cytosine, azacytosine, 6-azo-thymine, 6-thio-guanine, 7-methylguanine, 7-methyladenine, 7-deazaguanine, 7-deazaguanosine, 7-deaza-adenine, 7-deaza-8-azaguanine, 8-azaguanine, 8-azaadenine, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, and 8-hydroxyl substituted adenines and guanines; N4-ethylcytosine, N-2 substituted purines, N-6 substituted purines, O-6 substituted purines, fluorinated nucleic acids, tricyclic pyrimidines, phenoxazine cytidine ([5,4-b][1,4] benzoxazin-2 (3H)-one), phenothiazine cytidine (1H-pyrimido [5,4-b][1,4] benzothiazin-2 (3H)-one), G-clamps, phenoxazine cytidine (9-(2-aminoethoxy)-H-pyrimido [5,4-b][1,4] benzoxazin-2 (3H)-one), carbazole cytidine (2H-pyrimido [4,5-b] indol-2-one), pyridoindole cytidine (H-pyrido [3′,2′: 4,5] pyrrolo [2,3-d] pyrimidin-2-one), 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methythio-N6-isopentenyladeninje, uracil-5oxyacetic acid, wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxacetic acid methylester, uracil-5-oxacetic acid, 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, and 2,6-diaminopurine and those in which the purine or pyrimidine base is replaced with a heterocycle.

14 . The isolated cell of claim 12 , wherein the heterologous nucleoside triphosphate transporter comprises an amino acid sequence that is at least about 90% identical to SEQ ID NO: 1.

15 . The isolated cell of claim 14 , further comprising a second unnatural nucleotide, wherein the first unnatural nucleotide and the second unnatural nucleotide each independently comprise a base or are selected from: 2-aminoadenin-9-yl, 2-aminoadenine, 2-F-adenine, 2-thiouracil, 2-thio-thymine, 2-thiocytosine, 2-propyl and alkyl derivatives of adenine and guanine, 2-amino-adenine, 2-amino-propyl-adenine, 2-aminopyridine, 2-pyridone, 2′-deoxyuridine, 2-amino-2′-deoxyadenosine 3-deazaguanine, 3-deazaadenine, 4-thio-uracil, 4-thio-thymine, uracil-5-yl, hypoxanthin-9-yl (I), 5-methyl-cytosine, 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 5-bromo, and 5-trifiuoromethyl uracils and cytosines; 5-halouracil, 5-halocytosine, 5-propynyl-uracil, 5-propynyl cytosine, 5-uracil, 5-substituted, 5-halo, 5-substituted pyrimidines, 5-hydroxycytosine, 5-bromocytosine, 5-bromouracil, 5-chlorocytosine, chlorinated cytosine, cyclocytosine, cytosine arabinoside, 5-fluorocytosine, fluoropyrimidine, fluorouracil, 5,6-dihydrocytosine, 5-iodocytosine, hydroxyurea, iodouracil, 5-nitrocytosine, 5-bromouracil, 5-chlorouracil, 5-fluorouracil, and 5-iodouracil, 6-alkyl derivatives of adenine and guanine, 6-azapyrimidines, 6-azo-uracil, 6-azo cytosine, azacytosine, 6-azo-thymine, 6-thio-guanine, 7-methylguanine, 7-methyladenine, 7-deazaguanine, 7-deazaguanosine, 7-deaza-adenine, 7-deaza-8-azaguanine, 8-azaguanine, 8-azaadenine, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, and 8-hydroxyl substituted adenines and guanines; N4-ethylcytosine, N-2 substituted purines, N-6 substituted purines, O-6 substituted purines, fluorinated nucleic acids, tricyclic pyrimidines, phenoxazine cytidine ([5,4-b][1,4] benzoxazin-2 (3H)-one), phenothiazine cytidine (1H-pyrimido [5,4-b][1,4] benzothiazin-2 (3H)-one), G-clamps, phenoxazine cytidine (9-(2-aminoethoxy)-H-pyrimido [5,4-b][1,4] benzoxazin-2 (3H)-one), carbazole cytidine (2H-pyrimido [4,5-b] indol-2-one), pyridoindole cytidine (H-pyrido [3′,2′: 4,5] pyrrolo [2,3-d] pyrimidin-2-one), 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methythio-N6-isopentenyladeninje, uracil-5oxyacetic acid, wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxacetic acid methylester, uracil-5-oxacetic acid, 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, and 2,6-diaminopurine and those in which the purine or pyrimidine base is replaced with a heterocycle.

16 . The isolated cell of claim 1 , wherein the cell is an Escherichia coli cell.

17 . The isolated cell of claim 12 , wherein the cell is an Escherichia coli cell.

18 . The isolated cell of claim 1 , wherein the first unnatural nucleotide is present in deoxyribonucleic acid (DNA).

19 . The isolated cell of claim 18 , wherein the DNA comprises at least one unnatural base pair (UBP), wherein the at least one UBP comprises the first unnatural nucleotide and a second unnatural nucleotide, wherein the second unnatural nucleotide comprises a base independently selected from:

20 . The isolated cell of claim 19 , wherein the first unnatural nucleotide and the second unnatural nucleotide each independently comprise a base selected from:

21 . The isolated cell of claim 1 , wherein the heterologous nucleoside triphosphate transporter comprises an amino acid sequence that is at least about 95% identical to SEQ ID NO: 1.

22 . The isolated cell of claim 12 , wherein the heterologous nucleoside triphosphate transporter comprises an amino acid sequence that is at least about 95% identical to SEQ ID NO: 1.

23 . The isolated cell of claim 1 , wherein the cell is a bacterial cell.

24 . The isolated cell of claim 12 , wherein the cell is a bacterial cell.

25 . An isolated bacterial cell comprising a heterologous nucleoside triphosphate transporter comprising an amino acid sequence that is at least about 85% identical to SEQ ID NO: 1, wherein the heterologous nucleoside triphosphate transporter is capable of transporting a triphosphate of an unnatural nucleotide into the isolated bacterial cell.

26 . The isolated bacterial cell of claim 25 , wherein the unnatural nucleotide comprises a base selected from:

27 . The isolated bacterial cell of claim 25 , wherein the unnatural nucleotide is an unnatural deoxyribonucleotide.

28 . The isolated bacterial cell of claim 27 , wherein the unnatural deoxyribonucleotide comprises a base

29 . The isolated bacterial cell of claim 25 , wherein the unnatural nucleotide is an unnatural ribonucleotide.

30 . The isolated bacterial cell of claim 29 , wherein the unnatural ribonucleotide comprises a base

31 . The isolated bacterial cell of claim 25 , wherein the heterologous nucleoside triphosphate transporter comprises an amino acid sequence that is at least about 90% identical to SEQ ID NO: 1.

32 . The isolated bacterial cell of claim 25 , wherein the heterologous nucleoside triphosphate transporter comprises an amino acid sequence that is at least about 95% identical to SEQ ID NO: 1.

33 . The isolated bacterial cell of claim 25 , wherein the isolated bacterial cell is an Escherichia bacterium.

34 . The isolated bacterial cell of claim 33 , wherein the Escherichia bacterium is Escherichia coli.

35 . The isolated bacterial cell of claim 25 , comprising a nucleotide sequence that encodes the heterologous nucleoside triphosphate transporter, wherein the nucleotide sequence comprises a nucleotide sequence that is at least about 85% identical to SEQ ID NO: 2.

36 . The isolated bacterial cell of claim 31 , comprising a nucleotide sequence that encodes the heterologous nucleoside triphosphate transporter, wherein the nucleotide sequence comprises a nucleotide sequence that is at least about 90% identical to SEQ ID NO: 2.

37 . The isolated bacterial cell of claim 32 , comprising a nucleotide sequence that encodes the heterologous nucleoside triphosphate transporter, wherein the nucleotide sequence comprises a nucleotide sequence that is at least about 90% identical to SEQ ID NO: 2.

38 . The isolated cell of claim 1 , wherein the heterologous nucleoside triphosphate transporter comprises an amino acid sequence that is 100% identical to SEQ ID NO: 1.

39 . The isolated cell of claim 12 , wherein the heterologous nucleoside triphosphate transporter comprises an amino acid sequence that is 100% identical to SEQ ID NO: 1.

40 . The isolated bacterial cell of claim 25 , wherein the heterologous nucleoside triphosphate transporter comprises an amino acid sequence that is 100% identical to SEQ ID NO: 1.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 4, 2022
From: ROMESBERG, FLOYD E.; MALYSHEV, DENIS A.
To: THE SCRIPPS RESEARCH INSTITUTE
Reel/Frame 060725/0359 →
Continuity (5)
Division 16591422 · Oct 2, 2019
Division 15302874
Provisional Application 61977439 · Apr 9, 2014
Provisional Application 61977430 · Apr 9, 2014
Related Publication 20230235339A1 · Jul 27, 2023
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