CpG oligonucleotide prodrugs, compositions thereof and associated therapeutic methods
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/00
C12N-015/117
출원번호
US-0721409
(2005-12-13)
등록번호
US-9809824
(2017-11-07)
국제출원번호
PCT/US2005/044935
(2005-12-13)
§371/§102 date
20070802
(20070802)
국제공개번호
WO2006/065751
(2006-06-22)
발명자
/ 주소
Verthelyi, Daniela
Beaucage, Serge L.
Grajkowski, Andrzej
출원인 / 주소
The United States of America, Represented by the Secretary, Department of Health and Human Services
대리인 / 주소
Klarquist Sparkman, LLP
인용정보
피인용 횟수 :
0인용 특허 :
78
초록▼
The present invention provides a CpG oligonucleotide prodrug that includes a thermolabile substituent on at least one nucleotide thereof. The present invention also provides compositions that include a carrier and a therapeutically effective amount of at least one CpG oligonucleotide prodrug. The pr
The present invention provides a CpG oligonucleotide prodrug that includes a thermolabile substituent on at least one nucleotide thereof. The present invention also provides compositions that include a carrier and a therapeutically effective amount of at least one CpG oligonucleotide prodrug. The present invention further provides therapeutic methods of using such thermolabile CpG oligonucleotide prodrugs and compositions thereof. The present invention further provides a method of inhibiting tetrad formation in a CpG oligonucleotide by functionalizing the CpG oligonucleotide with one or more thermolabile substituents.
대표청구항▼
1. A CpG oligonucleotide prodrug comprising a CpG oligonucleotide that has a poly-G tail at the 3′-end of the oligonucleotide and a thermolabile substituent bonded thereto, wherein the thermolabile substituent is bonded to the non-bridging oxygen atom of a deoxyguanosine phosphate, phosphorothioate,
1. A CpG oligonucleotide prodrug comprising a CpG oligonucleotide that has a poly-G tail at the 3′-end of the oligonucleotide and a thermolabile substituent bonded thereto, wherein the thermolabile substituent is bonded to the non-bridging oxygen atom of a deoxyguanosine phosphate, phosphorothioate, or phosphoroselenoate diester present in the poly-G tail in an amount sufficient to inhibit G-tetrad formation, wherein the CpG oligonucleotide that has a poly-G tail forms a tetraplex in the absence of the thermolabile substituent, and, wherein the thermolabile substituent is of the formula: wherein:R2, R2′, R3 and R3′are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl, or R2 or R2′, in combination with R3 or R3′, together with the carbon atoms to which they are bonded, comprise a cyclic substituent of the formula: wherein p is an integer from 0-6 and a-d are the same or different and each is selected from the group consisting of H, an alkyl, a nitro, a dialkylamino, an alkoxy, an alkylthio, a cyano and a halogen;Z is O, S, NR4a, CR4aR4a′or CR4aR4a′CR4bR4b′, wherein R4a, R4a′, R4b and R4b′ are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl; andY is CH2R1 or C(X)H wherein X is O or S, and R1 is H, R1a, OR1a, SR1a or NR1aR1a′, wherein R1a and R1a′are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl;wherein R1a, R1a′, R2, R2′,R3, R3′, R4a, R4a′,R4b and R4b′ are unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of OR5, SR5, CN, NO2, N3, and a halogen, wherein R5 is H or an alkyl. 2. The CpG oligonucleotide prodrug of claim 1, wherein R2, R2′, R3 and R3′are all hydrogen. 3. The CpG oligonucleotide prodrug of claim 1, wherein Z is CR4aR4a′or CR4aR4a′CR4bR4b′and R4a, R4a′, R4b and R4b′are all hydrogen. 4. The CpG oligonucleotide prodrug of claim 1, wherein Z is NR4a and R4a is alkyl. 5. The CpG oligonucleotide prodrug of claim 1, wherein Y is CH2R1 or C(O)H and R1 is H, OH, R1a, SR1a or NR1aR1a′, wherein R1a is alkyl and R1a′is H. 6. The CpG oligonucleotide prodrug of claim 5, wherein R1a is methyl or tert-butyl. 7. The CpG oligonucleotide of claim 2, wherein the thermolabile substituent is selected from the group consisting of: 8. The CpG oligonucleotide prodrug of claim 7, wherein the thermolabile substituent is selected from the group consisting of: 9. The CpG oligonucleotide prodrug of claim 1, comprising a K-type oligodeoxynucleotide sequence, a B-type oligodeoxynucleotide sequence, an A-type oligodeoxynucleotide sequence, or a D-type oligodeoxynucleotide sequence. 10. The CpG oligonucleotide prodrug of claim 7, comprising a K-type oligodeoxynucleotide sequence, a B-type oligodeoxynucleotide sequence, an A-type oligodeoxynucleotide sequence, or a D-type oligodeoxynucleotide sequence. 11. The CpG oligonucleotide prodrug of claim 1, wherein at least one nucleotide-of-the CpG oligonucleotide comprises a thermolabile phosphodiester protecting group. 12. The CpG oligonucleotide prodrug of claim 1, wherein the CpG oligonucleotide comprises the nucleic acid sequence of SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8. 13. The CpG oligonucleotide prodrug of claim 1, wherein the CpG oligonucleotide induces cytokine production when the CpG oligonucleotide prodrug is administered to a human. 14. The CpG oligonucleotide prodrug of claim 1, wherein the CpG oligonucleotide induces cytokine production when the CpG oligonucleotide prodrug is administered to a mouse. 15. A pharmaceutical composition comprising a carrier and a therapeutically effective amount of at least one CpG oligonucleotide prodrug of claim 1. 16. A pharmaceutical composition comprising a carrier and a therapeutically effective amount of at least one CpG oligonucleotide prodrug of claim 7. 17. A pharmaceutical composition comprising a carrier and a therapeutically effective amount of at least one CpG oligonucleotide prodrug of claim 8. 18. The CpG oligonucleotide prodrug of claim 7, wherein at least one nucleotide of the CpG oliogonucleotide comprises a thermolabile phosphodiester protecting group. 19. A pharmaceutical composition comprising a carrier and a therapeutically effective amount of at least one CpG oligonucleotide prodrug of claim 2. 20. A pharmaceutical composition comprising a carrier and a therapeutically effective amount of at least one CpG oligonucleotide prodrug of claim 4. 21. A method of inducing production of a cytokine in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 15, thereby inducing production of the cytokine in the subject. 22. The method of claim 21, wherein the cytokine is interleukin (IL)-10, interferon (IFN)-α or IFN-γ. 23. The method of claim 21, wherein the cytokine is IL-6 or IFN-α. 24. The method of claim 21, wherein the GpG oligonucleotide comprises a K-type oligodeoxynucleotide sequence, a B-type oligodeoxynucleotide sequence, an A-type oligodeoxynucleotide sequence, or a D-type oligodeoxynucleotide sequence. 25. The method of claim 21, wherein the thermolabile substituent is selected from the group consisting of:
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