Complex and method for enhancing nuclear delivery
AssigneeOligomer Sciences AB
InventorsEdvard Smith, Pedro Moreno, Roger Strömberg, Malgorzata Wenska
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Abstract
The use of at least one nucleic acid based nuclear localization signal including a natural or synthetic m3G-CAP is shown to increase transmembrane transport of a molecular cargo, in particular large molecules, into the nucleus. The use of natural and synthetic m3G-CAP is disclosed and the effect shown with a natural RNA 5′ end nuclear localization signal composed of a 2,2,7-trimethylguanosine CAP (m3G-CAP) coupled to fluorescent Streptavidin in one example, and an antisense oligonucleotide in another. A methylenephosphonate modified m3G-CAP is shown to have improved stability in human serum and in cytosolic extract.
Claims9
A complex for facilitating transmembrane transport of a molecular cargo into the nucleus of a mammalian cell, wherein said complex comprises a molecular cargo coupled to a synthetic m3G-CAP or an analogue thereof, wherein said molecular cargo is linked by covalent or non-covalent attachment to at least one modified 2,2,7-trimethylguanosine CAP structure as specified in Formula (I)
- wherein
- R1 is a cargo attached directly or a mono-, di- or oligonucleotide (modified or unmodified) followed by a cargo unless the cargo is attached through R2 then R1 is a hydroxyl or a phosphate mono or diester;
- R2 is methyl or any unsubstituted or substituted alkyl group or is a cargo attached directly or a mono-, di- or oligonucleotide (modified or unmodified) followed by a cargo;
- R3 is O or CH2;
- R4 is O or CH2;
- R5 is O or CH2;
- R6 is O or CH2;
- X is OH or SH, or salts thereof;
- Y is OH or SH, or salts thereof;
- Z is OH or SH, or salts thereof;
- R7 is O, Or CH2;
- R8 is NH2, H, or OH;
- R9 is H, NH2 or OH;
- R10 is OH, or F;
- and
- R11 is OH, Or OCH3, and
- wherein “base” is a purine or a pyrimidine base selected from uracil, cytosine, adenine, quinine or thymine or derivatives thereof.
A complex for facilitating transmembrane transport of a molecular cargo into the nucleus of a mammalian cell, wherein said complex comprises a molecular cargo coupled to a synthetic m3G-CAP or an analogue thereof, wherein said molecular cargo is linked by covalent or non-covalent attachment to at least one modified 2,2,7-trimethylguanosine CAP structure as specified in Formula (I)
- wherein
- R1 is a cargo attached directly or a mono-, di- or oligonucleotide (modified or unmodified) followed by a cargo unless the cargo is attached through R2 then R1 is a hydroxyl or a phosphate mono or diester;
- R2 is methyl or any unsubstituted or substituted alkyl group or is a cargo attached directly or a mono-, di- or oligonucleotide (modified or unmodified) followed by a cargo;
- R3 is O or CH2;
- R6 is O or CH2;
- X is OH or SH, or salts thereof;
- Y is OH or SH, or salts thereof;
- Z is OH or SH, or salts thereof;
- R7 is O, Or CH2;
- R8 is NH2, H, or OH;
- R9 is H, NH2 or OH;
- R10 is OH, or F;
- and
- R11 is OH, Or OCH3,
- wherein R4 and R5 are CH2, or R5 is O when R4 is CH2, or R4 is O when R5 is CH2, and
- wherein “base” is a purine or a pyrimidine base selected from uracil, cytosine, adenine, quinine or thymine or derivatives thereof.
Dependencies are inferred from the claim text.