Polypeptide-nucleic acid conjugates and uses thereof

A nucleic acid and compound technology, applied in the fields of applications, peptides, and decapeptides, can solve problems such as gene silencing

Inactive Publication Date: 2011-01-12
ANGLACHEM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a result, the protein encoded by the mRNA is no longer produced, causing gene silencing

Method used

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  • Polypeptide-nucleic acid conjugates and uses thereof
  • Polypeptide-nucleic acid conjugates and uses thereof
  • Polypeptide-nucleic acid conjugates and uses thereof

Examples

Experimental program
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preparation example Construction

[0230] Preparation of Peptide Derivatives and Mimetic Peptides

[0231]In addition to polypeptides consisting only of naturally occurring amino acids, the invention also includes peptidomimetics or polypeptide analogs. Peptide analogs are generally used as non-peptide drugs in the pharmaceutical industry, and their properties are similar to those of template polypeptides. Non-peptidic compounds are known as "peptidomimetics" or "peptidomimetics" (Fauchere et al., Infect. Immun. 54:283-287, 1986; Evans et al, J.Med.Chem. 30:1229-1239, 1987) . Peptidomimetics that are structurally related to a therapeutically useful peptide or polypeptide can be used to produce equivalent or enhanced therapeutic or prophylactic effects. Typically, a peptidomimetic is structurally similar to a paradigm polypeptide (i.e., a polypeptide having biological or pharmaceutical activity), such as a polypeptide that binds a naturally occurring receptor, but has one or more peptide linkages , the peptid...

Embodiment 1

[0324] Peptide-Nucleic Acid Binding

[0325] Incubate at 90°C in annealing buffer (100 mM potassium acetate, 30 mM HEPES-KOH pH 7.2, 2 mM magnesium acetate) with 35 μM single-stranded siRNA sequence encoding epidermal growth factor receptor (EGFR) containing a 5' thiol group RNA oligonucleotides were used for 1 min, followed by incubation at 37°C for 1 h. In Eppendorf tubes, desalt the annealed siRNA oligonucleotides by incubating the hybridization mix well in pre-made 1% agarose in 100 mM glucose for 7 min on ice (reserve 100 μL of Spare (tip) and allow it to adjust (set)). To the desalted siRNA molecules, 1 volume of reaction buffer (10 mM HEPES, 1 mM EDTA, pH 8.0) was added to adjust the final concentration of siRNA to 17.5 μM. Equimolar amounts of EGFR siRNA, angiopeptide-2 polypeptide and thiol oxidant diamide (sigma, USA) were mixed and incubated at 40° C. for 1 h. The polypeptide-nucleic acid conjugate / diamide solution is mixed with culture media and applied to targe...

Embodiment 2

[0327] The N-terminus and C-terminus of the siRNA are bound to the peptide carrier

[0328] Such as Figure 4 As shown, peptide vectors with N-terminal or C-terminal cysteines (eg, SEQ ID NO: 113 and 114) can be bound to SH-siRNA directly or through a linker. Depending on the linker chosen, this linkage can be cleavable or non-cleavable. Here, the peptide carrier is bound to the sense strand of the siRNA duplex.

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Abstract

The present invention is directed to polypeptide-nucleic acid conjugates. These conjugates can allow for targeted application of a therapeutic RNAi agent across the blood-brain barrier to treat, for example, a cancer, neurodegenerative disease, or lysosomal storage disorder.

Description

technical field [0001] The present invention relates to improvements in the field of drug delivery. More specifically, the invention relates to polypeptide-nucleic acid conjugates and their use in the transport of nucleic acids across the blood-brain barrier or into other tissues of a subject in the treatment of diseases such as cancer, neurodegenerative diseases, and lysosomal storage diseases . Background technique [0002] In the development of new treatments for brain pathologies, the blood-brain barrier (BBB) ​​is considered a major obstacle to the potential use of drugs for the treatment of central nervous system (CNS) diseases. In 1998, the global market of CNS drugs was 33 billion US dollars, which was about half of the global market of cardiovascular drugs. In the United States alone, the number of patients with CNS diseases was almost twice that of patients with cardiovascular diseases. The reason for this imbalance is, in part, that more than 98% of all potentia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/00A61K47/48A61K48/00A61P25/28A61P35/00A61P35/04C07H21/00C07K14/00C07K7/06C07K7/08A61K31/337C12N15/18C12N15/54C12N15/57C12N15/87C12N15/113
CPCC12N2320/32C12N2310/3513A61K48/0025C12N2310/14A61K47/48246C12N15/1138C07K7/08C12N2810/50C12N2810/40A61K47/48092A61K48/0041A61K47/48338A61K47/549A61K47/64A61K47/65A61P3/10A61P9/10A61P21/02A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/18A61P25/28A61P27/02A61P35/00A61P35/02A61P35/04
Inventor 理查德·贝利沃米歇尔·德默勒克里斯蒂安·切安东尼·雷吉纳
Owner ANGLACHEM INC
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