Oligonucleotide compositions and methods of making the same
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/00
C12N-015/113
C12P-019/34
출원번호
US-0699902
(2015-04-29)
등록번호
US-9796747
(2017-10-24)
발명자
/ 주소
Ramiya, Premchandran H.
출원인 / 주소
Geron Corporation
대리인 / 주소
Foulds, Glenn J.
인용정보
피인용 횟수 :
0인용 특허 :
49
초록▼
The present disclosure provides a solid phase method of making oligonucleotides via sequential coupling cycles including at least one coupling of a dinucleotide dimer subunit to a free 3′-terminal group of a growing chain. The oligonucleotides include at least two nucleoside subunits joined by a N3′
The present disclosure provides a solid phase method of making oligonucleotides via sequential coupling cycles including at least one coupling of a dinucleotide dimer subunit to a free 3′-terminal group of a growing chain. The oligonucleotides include at least two nucleoside subunits joined by a N3′→P5′ phosphoramidate linkage. The method may include the steps of (a) deprotecting the protected 3′ amino group of a terminal nucleoside attached to a solid phase support, said deprotecting forming a free 3′ amino group; (b) contacting the free 3′ amino group with a 3′-protected amino-dinucleotide-5′-phosphoramidite dimer in the presence of a nucleophilic catalyst to form an internucleoside N3′→P5′ phosphoramidite linkage; and (c) oxidizing (e.g., sulfurizing) the linkage. The compositions produced by the subject methods may include a reduced amount of one or more (N−x) oligonucleotide products. Also provided are pharmaceutical compositions including the subject oligonucleotide compositions.
대표청구항▼
1. A method of synthesizing a polynucleotide, the method comprising the steps of: (a) deprotecting the protected 3′ amino group of a terminal nucleoside attached to a solid phase support, said deprotecting forming a free 3′ amino group;(b) contacting the free 3′ amino group with a 3′-protected amino
1. A method of synthesizing a polynucleotide, the method comprising the steps of: (a) deprotecting the protected 3′ amino group of a terminal nucleoside attached to a solid phase support, said deprotecting forming a free 3′ amino group;(b) contacting the free 3′ amino group with a 3′-protected amino-dinucleotide phosphoramidate-5′-phosphoramidite dimer in the presence of a nucleophilic catalyst to form an internucleoside N3′→P5′ phosphoramidite linkage; and(c) oxidizing the linkage. 2. The method of claim 1, further comprising: (a) deprotecting the protected 3′ amino group of a terminal nucleoside attached to a solid phase support, said deprotecting forming a free 3′ amino group;(b) contacting the free 3′ amino group with a 3′-protected aminonucleoside-5′-phosphoramidite monomer in the presence of a nucleophilic catalyst to form an internucleoside N3′→P5′ phosphoramidite linkage; and(c) oxidizing the linkage. 3. The method of claim 1, wherein the 3′-protected amino-dinucleotide phosphoramidate-5′-phosphoramidite dimer has the formula: wherein X is O or S and B1 and B2 are each independently a purine, a protected purine, a pyrimidine or a protected pyrimidine, or an analog thereof. 4. The method of claim 3, wherein X is S. 5. The method of claim 4, wherein the polynucleotide comprises a sequence of nucleoside subunits complementary to the RNA component of human telomerase, and wherein at least two of the nucleoside subunits are joined by a N3′→P5′ phosphoramidate inter-subunit linkage. 6. The method of claim 5, wherein the N3′→P5′ phosphoramidate inter-subunit linkage is a N3′→P5′ thiophosphoramidate inter-subunit linkage having the structure: 3′-NH—P(S)(OR)—O-5′wherein R is selected from the group consisting of hydrogen, an alkyl, a substituted alkyl, an aryl, a substituted aryl and a phosphate protecting group, or a salt thereof. 7. The method of claim 1, wherein oxidizing the linkage comprises sulfurization to produce a thiophosphoramidate linkage. 8. The method of claim 1, wherein oxidizing the linkage produces an oxophosphoramidate linkage. 9. The method of claim 3, wherein the B1 and B2 are each independently selected from protected adenine, protected cytosine, protected guanine, thymine and uracil. 10. The method of claim 9, wherein the B1 and B2 are each independently selected from A(Bz), A(DMF), C(Bz), G(isobutyryl), T and U. 11. The method of claim 1, wherein the 3′-protected amino-dinucleotide phosphoramidite-5′-phosphoramidite dimer is described by the formula X1X2, wherein X1 and X2 are independently selected from protected adenine, protected cytosine, protected guanine, thymine and uracil. 12. The method of claim 2, wherein the 3′-protected aminonucleoside-5′-phosphoramidite monomer is selected from protected adenine, protected cytosine, protected guanine, thymine and uracil.
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이 특허에 인용된 특허 (49)
Fung Steven (Palo Alto CA) Woo Sam L. (Redwood City CA) Smith Lloyd M. (South Pasadena CA), Amino-derivatized phosphite and phosphate linking agents, phosphoramidite precursors, and useful conjugates thereof.
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Hostetler Karl Y. (Del Mar CA) Kumar Raj (San Diego CA), Method of converting a drug to an orally available form by covalently bonding a lipid to the drug.
Shay Jerry W. ; Wright Woodring E. ; Piatyszek Mieczyslaw A. ; Corey David R. ; Norton James C., Modulation of mammalian telomerase by peptide nucleic acids.
Hanecak,Ronnie C.; Anderson,Kevin P.; Bennett,C. Frank; Chiang,Ming Yi; Brown Driver,Vickie L.; Ecker,David J.; Vickers,Timothy A.; Wyatt,Jacqueline R., Modulation of telomere length by oligonucleotides having a G-core sequence.
Letsinger Robert L. (Wilmette IL) Gryaznov Sergei M. (San Mateo CA), Oligodeoxyribonucleotides including 3′-aminonucleoside-phosphoramidate linkages and terminal 3′-amino groups.
Gryaznov Sergei M. (San Mateo CA) Schultz Ronald G. (Fremont CA) Chen Jer-kang (Palo Alto CA), Oligonucleotide N3′-P5′phosphoramidates: hybridization and nuclease resistance properties.
Gryaznov Sergei M. (San Mateo CA) Schultz Ronald G. (Fremont CA) Chen Jer-Kang (Palo Alto CA), Oligonucleotide N3′→P5′phosphoramidates: hybridization and nuclease resistance properties.
Gryaznov Sergei M. (San Mateo CA) Schultz Ronald G. (Fremont CA) Chen Jer-kang (Palo Alto CA), Oligonucleotide N3→P5′phosphoramidates: triplex DNA formation.
Bischofberger Norbert ; Kent Ken ; Wagner Rick ; Buhr Chris ; Lin Kuei-Ying, Oligonucleotides and their analogs capable of passive cell membrane permeation.
Hanecak Ronnie C. ; Anderson Kevin P. ; Bennett C. Frank ; Chiang Ming-Yi ; Brown-Driver Vickie L. ; Ecker David J. ; Vickers Timothy A. ; Wyatt Jacqueline R. ; Imbach Jean Louis,FRX, Oligonucleotides having a conserved G4 core sequence.
Letsinger Robert L. (316 3rd St. Wilmette IL 60091) Gryaznov Sergei M. (2 Clark Dr. San Mateo CA 94401), Oligonucleotides having modified internucleoside linkages.
Hirschbein Bernard L. ; Fearon Karen L. ; Gryaznov Sergei M. ; McCurdy Sarah N. ; Nelson Jeffery S. ; Schultz Ronald G., Solid phase synthesis of oligonucleotide N3'-P5' phosphoramidates.
Hirschbein Bernard L. ; Fearon Karen L. ; Gryaznov Sergei M. ; McCurdy Sarah N. ; Nelson Jeffrey S. ; Schultz Ronald G., Synthons for synthesis of oligonucleotide N3-P5 phosphoramidates.
Matsuo, Kazunori; Suzuki, Yasutaka; Takahashi, Masakazu; Nishio, Yoshimichi; Watarihana, Hideaki; Goto, Hiroki; Takahashi, Teruo; Furukawa, Kiyoshi; Kobayashi, Hiroyuki; Kubota, Hidetsugu; Abe, Takuy, System for reproducing information recorded on an information recording medium.
Summerton James E. (Corvallis OR) Weller Dwight D. (Corvallis OR), Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages.
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