254 results about "Modified nucleosides" patented technology

A modification template for improving the inhibitory effect of a double-stranded oligonucleotide on a target gene, a combination thereof and the use thereof. The double-stranded oligonucleotide is an siRNA and contains a sense strand and an antisense strand, and each nucleotide of the sense strand and antisense strand is a modified nucleotide. The double-stranded oligonucleotide is modified with a special modification template, and has a significantly improved inhibition rate on a target gene compared with a basic sequence.

The present invention relates to variants of Terminal deoxynucleotidyl Transferase (TdT), each of which (i) has an amino acid sequence similarity to SEQ ID NO: 2, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33 or 35 with corresponding amino acid substitutions, (ii) is capable of synthesizing a nucleic acid fragment without a template and (iii) is capable of incorporating a modified nucleotide into the nucleic acid fragment.

The technology described herein relates to 5'-modified nucleosides, nucleotides, oligonucleotides and double-stranded RNAs, e.g., siRNAs, and kits comprising them and methods of their use for inhibiting target genes.

There is provided an oligonucleotide or a pharmaceutically acceptable salt thereof with a novel chemical modification pattern, which has a RNA interfering action and / or a gene expression suppressing action. A sense strand region has a specific modification pattern with a 3'-modified nucleoside, and an antisense strand region has, in a specific region, a modification pattern in which DNA, RNA, 2'-O,4'-C-bridging-modified nucleosides, 2'-MOE RNA or the like are appropriately combined.

This invention provides purified preparations of an RNA, oligoribonucleotide, or polyribonucleotide comprising a modified nucleoside, and methods of assessing purity of purified preparations of an RNA, oligoribonucleotide, or polyribonucleotide comprising a modified nucleoside.

The present disclosure relates to siRNA for inhibiting hepatitis B virus and uses thereof. In particular to an oligonucleotide for inhibiting HBV or a pharmaceutically acceptable salt thereof, the oligonucleotide comprises an antisense strand, the antisense strand comprises at least one modified nucleotide, and the nucleotide sequence of the antisense strand comprises a sequence or fragment as shown in any one of SEQ ID NO: 3-35. According to the present invention, the siRNA provides significant inhibition effects for HBsAg, HBV DNA and HBeAg generated by cccDNA and host genome integrated HBV DNA in vivo and in vitro, the drug effect is lasting, and compared with the original sequence, the optimized sequence improves the inhibition effect and the drug effect period, and reduces the off-target toxicity;

Provided is an siRNA for inhibiting the gene expression of complement factor B (CFB), or a pharmaceutical composition or conjugate containing the siRNA. The siRNA contains a sense strand and an antisense strand. Each nucleotide in the siRNA is an independent modified or unmodified nucleotide. The sense strand contains a segment of nucleotide sequence I, and the nucleotide sequence I and a nucleotide sequence show in SEQ ID NO: 1 have an equal length and differ by no more than 3 bases. The antisense strand contains a nucleotide sequence II, and the nucleotide sequence II and a nucleotide sequence shown in SEQ ID NO: 2 have an equal length and differ by no more than 3 bases. The siRNA or the pharmaceutical composition or conjugate containing the siRNA can effectively treat and / or prevent diseases related to the mRNA level of the gene expression of the CFB.

The invention discloses a double-chain miRNA, a pharmaceutical composition containing the same, an anti-aging product and application of the double-chain miRNA. The double-stranded miRNA comprises a chemically modified sense strand with a sequence shown as SEQ ID NO: 1 and a chemically modified antisense strand with a sequence shown as SEQ ID NO: 2, wherein the chemical modification of the sense strand and the antisense strand each comprises a 2 '-substituted nucleotide and a modified nucleotide bond; the chemically modified nucleotide bond is at least located at one or more of the 1st-3rd and 20th-23rd sites of the sequence shown as SEQ ID NO: 1 and / or SEQ ID NO: 2. The double-chain miRNA is good in stability and has a remarkable treatment effect on skin cell photoaging, Alzheimer's disease, articular cartilage injury, diabetes, non-alcoholic fatty liver disease, androgenetic alopecia, cirrhosis and chronic nephritis. In short, the effect and the stability of the product are both considered, and the application prospect is good.

The invention provides double-stranded oligonucleotide for inhibiting LPA gene expression and application of the double-stranded oligonucleotide, and relates to the technical field of nucleic acid drugs. The double-stranded oligonucleotide comprises a positive-sense strand and an antisense strand, wherein the positive-sense strand comprises a nucleotide sequence which is the same as or basically the same as at least 15 continuous nucleotides in the sequence as shown in SEQ ID NO.1, and the antisense strand comprises at least 17 nucleotides and is complementary or basically complementary with the positive-sense strand to form a duplex region; each nucleotide of the double-stranded oligonucleotide is independently selected from an unmodified or modified nucleotide. The double-stranded oligonucleotide can inhibit LPA gene expression and can treat siRNA drugs of diseases related to LPA gene expression, such as cardiovascular and cerebrovascular diseases.

The present invention relates to the technical field of nucleic acid drugs. Disclosed are a double-stranded oligonucleotide inhibiting LPA gene expression and the use thereof. The double-stranded oligonucleotide comprises a sense strand and an antisense strand, wherein the sense strand contains a nucleotide sequence that is identical or substantially identical to at least 15 consecutive nucleotides in the sequence as shown in SEQ ID NO. 1, and the antisense strand contains at least 17 nucleotides and is complementary or substantially complementary to the sense strand to form a duplex region. Each nucleotide of the double-stranded oligonucleotide is independently selected from unmodified or modified nucleotides. The double-stranded oligonucleotide can inhibit LPA gene expression and solve the problem of an siRNA drug for treating LPA gene expression related diseases such as cardiovascular and cerebrovascular diseases.

The present disclosure provides modified nucleosides, nucleotides, and nucleic acids, and methods of using thereof.

The invention relates to the field of biological medicines, and particularly provides 5 '-phosphate modified nucleoside as well as a preparation method and application thereof. The invention provides a modified nucleoside compound, which has a structure as shown in a formula (I), or is a pharmaceutically acceptable salt or stereoisomer of the compound with the structure as shown in the formula (I). The oligonucleotide containing the modified nucleoside compound provided by the invention has a remarkably enhanced drug curative effect. # imgabs0 #

The present invention relates to variants of Terminal deoxynucleotidyl Transferase (TdT), each of which (i) has an amino acid sequence similarity to SEQ ID NO: 2, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33 or 35 with corresponding amino acid substitutions, (ii) is capable of synthesizing a nucleic acid fragment without a template and (iii) is capable of incorporating a modified nucleotide into the nucleic acid fragment.

The invention belongs to the field of biological medicine, and relates to siRNA and a conjugate for inhibiting APP gene expression, the siRNA comprises a positive-sense strand and an antisense strand, the positive-sense strand comprises a nucleotide sequence I, and the antisense strand comprises a nucleotide sequence II; each nucleotide in the nucleotide sequence I and the nucleotide sequence II is modified or unmodified nucleotide; the nucleotide sequence I and the nucleotide sequence II are at least partially reversely complementary to form a double-stranded region; the nucleotide sequence I is basically consistent with a first section of nucleotide sequence, and the first section of nucleotide sequence is a section of nucleotide sequence with the length of at least 19 nucleotides in mRNA expressed by an APP gene. The siRNA can specifically induce degradation of APP mRNA, so that synthesis of APP in the liver is inhibited, APP protein is induced to be reduced durably, pathological deposition of Abeta and other related toxic proteins is reduced, and the siRNA has a good patent medicine prospect.

Polynucleotides, such as aptamers, comprising at least first one 5-position modified pyrimidine and at least one second 5-position modified pyrimidine are provided, wherein the first and second 5-position modified pyrimidines are different. Methods of selecting and using such polynucleotides, such as aptamers, are also provided.

The present disclosure relates to novel destabilizing molecules, such as a butadiol moiety, modified nucleosides incorporating the butadiol moiety, modified nucleotides incorporating the butadiol moiety, and oligonucleotides and RNAi agents comprising such modified nucleotides that improve selectivity and / or reduce off target effects while maintaining or improving knockdown of on target gene expression.

The invention relates to a nucleotide monomer compound and application thereof in nucleic acid interference (RNAi) drug molecules. After the nucleotide monomer is introduced into the siRNA antisense strand seed region, the potential off-target effect of the antisense strand seed region can be remarkably reduced, and the activity of siRNA can be maintained or improved, so that target gene mRNA is silenced with higher selectivity, the safety window of siRNA drugs is expanded, the druggability of siRNA can be improved, and the siRNA activity can be improved. Therefore, related diseases caused by the target gene mRNA can be treated more effectively. # imgabs0 #

An siRNA capable of inhibiting the expression of apolipoprotein C3 (APOC3) gene, comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand are respectively composed of nucleotide sequence I or nucleotide sequence II comprising 19 modified or unmodified nucleotides, and the nucleotide sequence I and the nucleotide sequence II are at least partially reverse complementary to form a double-stranded region, and the nucleotide sequence II is at least partially reverse complementary to a nucleotide sequence segment in the mRNA of APOC3 gene expression; in the direction from the 5'-end to the 3'-end, at least one of the 3-6th nucleotides of the nucleotide sequence II is a stabilized modified nucleotide. The siRNA as described above, as well as the pharmaceutical composition and siRNA conjugate comprising the siRNA, can effectively treat and / or prevent diseases or disorders related to APOC3 gene expression, and have a significantly reduced off-target effect.

Described herein are modified RNA molecules where a 3′-stabilizing region is covalently attached to the RNA, and where the 3′-stabilizing region comprises one or more modified nucleosides. Methods of synthesizing said RNAs are also provided herein.

The invention provides a nucleoside phosphoramidite compound as shown in a formula I. The invention further provides a preparation method of the nucleoside phosphoramidite compound. The nucleoside phosphoramidite compound disclosed by the invention can be introduced into the head and tail ends and / or the middle of oligonucleotide, the stability of the oligonucleotide is enhanced while the biological function of the oligonucleotide is enhanced or basically maintained, and the continuous acting time is prolonged.

The present disclosure relates to a nucleoside analogue and a use thereof. The nucleoside analogue is a compound shown in formula (Ia) or a prodrug thereof. The nucleoside analogue can enhance targeted delivery of oligonucleotide drugs to nervous system cells, thereby increasing the inhibition rate of the oligonucleotide drugs delivered in a targeted manner on expression of specific genes in the nervous system cells, or enabling the oligonucleotide drugs delivered in a targeted manner to achieve the purpose of preventing and / or treating pathological conditions or diseases caused by abnormal expression of the specific genes in the nervous system cells. The present disclosure also relates to a nucleotide analogue-containing double-stranded oligonucleotide and a use thereof. The double-stranded oligonucleotide comprises a sense strand and an antisense strand, each strand has 17-25 modified and / or unmodified nucleotides, and the antisense strand and the sense strand are complementary to form a duplex region; the sense strand and / or the antisense strand contains at least one nucleotide analogue represented by the structure of formula (100), or a tautomer, or stereoisomer, or pharmaceutically acceptable salt thereof; the double-stranded oligonucleotide can effectively treat and / or prevent pathological conditions or diseases caused by abnormal expression of specific genes in nervous system cells.

The invention discloses base-modified mRNA (messenger Ribonucleic Acid) and application thereof in a cell-free protein synthesis system, and belongs to the technical field of nucleic acid modification. Natural nucleoside triphosphate is completely replaced by different types of basic group modified nucleoside triphosphate, mRNA with different chemical modifications is obtained through an in-vitro transcription method and purification, and the mRNA is put into an in-vitro cell-free protein synthesis system for reaction. A reaction element recombination system-PURE system based on prokaryote Escherichia coli purified protein and an eukaryote CFPS system taking rabbit reticulated red lysate as a material are mainly selected to detect the corresponding translation efficiency of mRNA modified by different bases in two cell-free protein synthesis systems respectively. Different regulatory activities may be shown in different cell-free protein synthesis systems when different modified nucleotides are doped into mRNA, base modified triphosphoric acid capable of improving the translation efficiency of an in-vitro protein synthesis system is screened out, and the stability of mRNA in the cell-free protein synthesis system and the corresponding protein expression level are improved.

Provided are a double‑stranded RNA composition for modulating DGAT2 expression, a conjugate thereof, a pharmaceutical composition comprising same, and a use thereof. The double-stranded RNA comprises a sense strand and an antisense strand, and each nucleotide in the double-stranded RNA is independently a modified or unmodified nucleotide; the sense strand comprises one nucleotide sequence selected from the nucleotide sequences shown in SEQ ID NOs: 1-86 or a nucleotide sequence having no more than 3 nucleotide differences from the above sequences, and the antisense strand comprises one nucleotide sequence selected from the nucleotide sequences shown in SEQ ID NOs: 87-172 or a nucleotide sequence having no more than 5 nucleotide differences from the above sequences. The double-stranded RNA, the conjugate thereof and the pharmaceutical composition comprising same can be delivered to the liver by means of small nucleic acid delivery technology, and are expected to provide a safer and more effective therapeutic plan for patients with MASH-associated metabolic diseases.

This disclosure relates to the modified 3' region elements that confer improved therapeutic properties including, but not limited to, increased stability, increased expression, and / or a reduced innate immune response when introduced into a population of cells, even in the absence of a 5'-cap. The disclosure also provides polynucleotides (e.g., RNA molecules) containing modified 3' regions. In some embodiments of the disclosure, the modified 3' regions contain modified adenosines (e.g., 2'-0-methoxy- adenosine, 2'-fluoro-adenosine, or locked nucleic acid (LNA)-adenosine) and / or a modified thymidine (e.g., inverted deoxythymidine). In some embodiments of the disclosure, the modified 3' region may contain one or more modified internucleoside linkages (e.g., a phosphorothioate linkage) or modified nucleobase (e.g., N1-methyl-pseudouridine). The polynucleotides of the disclosure may be used to express a desired polypeptide in a subject, such as a subject having a disease or condition associated with a deficiency in the corresponding endogenous polypeptide.

The disclosure relates to a method for sequencing of a DNA strand, the method includes (S200) providing a double-stranded DNA fragment with a first strand and a second strand, the DNA strand to be sequenced corresponding to the first strand or the second strand, (S300A) connecting the first and second strands with a first hairpin oligonucleotide and a second hairpin oligonucleotide, (S500A) amplifying the ligated product obtained in step (S300A) using rolling circle amplification (RCA), (S600A) amplifying the ligated product obtained in step (S300A) using RCA or the amplicons obtained in step (S500A) using primer extension using a first group of redox-modified nucleotides and a second group of redox-modified nucleotides, and (S800A) determining the sequence of the DNA strand by sequencing the amplicons (80) obtained in step (S600A) using an electrochemical sequencing method.

Provided herein are RNA molecules (e.g. self-amplifying messenger ribonucleic acids (samRNA)) comprising modified nucleotides, such as N1-methyl-pseudouridine.

This application relates to mutant polymerases. This application discloses mutant phage-type RNA polymerases, such as a mutant T7, SP6, and T3 RNA polymerase, may use 2′-modified nucleoside triphosphates or deoxynucleotide triphosphates as substrates. Methods for producing nucleic acid molecules using these mutant polymerases are also disclosed.

Described herein are novel cap analogs of Formula (I) and compositions, and methods of using the same. Also described herein is an RNA molecule comprising a 5'-cap, wherein the 5'-cap includes a cap analog as described herein. Methods of inducing a therapeutic effect in a subject are also described herein, the methods including a step of administering to the subject a cap analog or RNA molecule comprising the cap analog as described herein.(I) wherein N is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, natural, modified, o unnatural nucleoside; with the proviso that N1 is not a modified or unmodified G nucleoside.

A single-stranded oligonucleotide having a length of 16-30 nucleotides. The single-stranded oligonucleotide and complement component C3 (CC3) mRNA have sufficient complementarity to mediate RNAi effect; each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, at least one nucleotide in the single-stranded oligonucleotide is a nucleotide X, and the at least one nucleotide is a fluoro-modified nucleotide; moreover, according to a direction from the 5' end to the 3' end, at least one nucleotide X is located after an eighth nucleotide and is spaced apart from the eighth nucleotide in the single-stranded oligonucleotide by 4-7 nucleotides; and each nucleotide X is a deoxynucleotide or an unmodified nucleotide. The present invention further relates to a double-stranded oligonucleotide comprising the single-stranded oligonucleotide as an antisense strand, an oligonucleotide conjugate, and a pharmaceutical composition.