Miravirsen

Last updated
Miravirsen
Miravirsen structure.svg
Clinical data
Other namesSPC3649
Routes of
administration
Intravenous or subcutaneous injection
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
  • RNA, (P-thio)((2'-O,4'-C-methylene)m5C-dC-(2'-O,4'-C-methylene)A-dT-dT-(2'-O,4'-C-methylene)G-(2'-O,4'-C-methylene)m5U-dC-dA-(2'-O,4'-C-methylene)m5C-dA-(2'-O,4'-C-methylene)m5C-dT-(2'-O,4'-C-methylene)m5C-(2'-O,4'-C-methylene)m5C)
CAS Number
PubChem CID
UNII
Chemical and physical data
Formula C151H185N49O83P14S14
Molar mass 4896.87 g·mol−1
  • CC1=CN([C@H]2CC(OP(O)(=S)OC[C@H]3O[C@H](CC3OP(O)(=S)OC[C@@]34COC([C@@H](O3)N3C=NC5=C3N=C(N)NC5=O)C4OP(O)(=S)OC[C@@]34COC([C@@H](O3)N3C=C(C)C(=O)NC3=O)C4OP(O)(=S)OC[C@H]3O[C@H](CC3OP(O)(=S)OC[C@H]3O[C@H](CC3OP(O)(=S)OC[C@@]34COC([C@@H](O3)N3C=CC(N)=NC3=O)C4OP(O)(=S)OC[C@H]3O[C@H](CC3OP(O)(=S)OC[C@@]34COC([C@@H](O3)N3C=CC(N)=NC3=O)C4OP(O)(=S)OC[C@H]3O[C@H](CC3OP(O)(=S)OC[C@@]34COC([C@@H](O3)N3C=CC(N)=NC3=O)C4OP(O)(=S)OC[C@]34COC(C3O)[C@@H](O4)N3C=CC(N)=NC3=O)N3C=C(C)C(=O)NC3=O)N3C=NC4=C3N=CN=C4N)N3C=NC4=C3N=CN=C4N)N3C=CC(N)=NC3=O)N3C=C(C)C(=O)NC3=O)[C@@H](COP(O)(=S)OC3C4OC[C@]3(COP(O)(=S)OC3C[C@@H](O[C@@H]3COP(O)(=S)OC3C5OC[C@]3(CO)O[C@H]5N3C=CC(N)=NC3=O)N3C=CC(N)=NC3=O)O[C@H]4N3C=NC4=C3N=CN=C4N)O2)C(=O)NC1=O

Miravirsen (INN; codenamed SPC3649) is an experimental drug for the treatment of hepatitis C, being developed by Santaris Pharma. As of 2017 it was in Phase II clinical trials. [1]

Miravirsen had been given by subcutaneous injection in early clinical trials as of 2017. [1] It is antisense to a human microRNA called miR-122. miR-122 ferries an argonaute protein to 5'-UTR region of viral RNA, where it binds, protecting the RNA from being destroyed by normally present nucleases; by binding to miR-122, miravirsen removes that protection and the virus RNA can be destroyed. [1] There is some evidence that the 5'-UTR region mutates under repeated exposure to miravirsen. [1]

Miravirsen is a modified oligonucleotide consisting of a chain of 15 nucleotides, the base sequence of which is designed to selectively bind to miR-122. [1] [2] Seven of the 15 sugar units are deoxyriboses, and the other eight are riboses with an additional bridge between the 2' oxygen and the 4' carbon atoms; this makes the molecule a locked nucleic acid. Furthermore, the phosphate units have been replaced by thiophosphates. [2]

The complete base sequence is

mC*-dC-A*-dT-dT-G*-mU*-dC-dA-mC*-dA-mC*-dT-mC*-mC* [d = 2'-deoxy, m = 5-methyl, * = 2'-O,4'-C-methylene, i.e. bridged or "locked" sugar]

with 3'→5' thiophosphate linkages. [2]

Related Research Articles

<span class="mw-page-title-main">Messenger RNA</span> RNA that is read by the ribosome to produce a protein

In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.

<span class="mw-page-title-main">Nucleic acid</span> Class of large biomolecules essential to all known life

Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). If the sugar is ribose, the polymer is RNA; if the sugar is deoxyribose, a variant of ribose, the polymer is DNA.

Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics. Commonly made in the laboratory by solid-phase chemical synthesis, these small fragments of nucleic acids can be manufactured as single-stranded molecules with any user-specified sequence, and so are vital for artificial gene synthesis, polymerase chain reaction (PCR), DNA sequencing, molecular cloning and as molecular probes. In nature, oligonucleotides are usually found as small RNA molecules that function in the regulation of gene expression, or are degradation intermediates derived from the breakdown of larger nucleic acid molecules.

<span class="mw-page-title-main">Locked nucleic acid</span> Biological molecule

A locked nucleic acid (LNA), also known as bridged nucleic acid (BNA), and often referred to as inaccessible RNA, is a modified RNA nucleotide in which the ribose moiety is modified with an extra bridge connecting the 2' oxygen and 4' carbon. The bridge "locks" the ribose in the 3'-endo (North) conformation, which is often found in the A-form duplexes. This structure provides for increased stability against enzymatic degradation. LNA also offers improved specificity and affinity in base-pairing as a monomer or a constituent of an oligonucleotide. LNA nucleotides can be mixed with DNA or RNA residues in a oligonucleotide.

<span class="mw-page-title-main">Directionality (molecular biology)</span> End-to-end chemical orientation of a single strand of nucleic acid

Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. In a single strand of DNA or RNA, the chemical convention of naming carbon atoms in the nucleotide pentose-sugar-ring means that there will be a 5′ end, which frequently contains a phosphate group attached to the 5′ carbon of the ribose ring, and a 3′ end, which typically is unmodified from the ribose -OH substituent. In a DNA double helix, the strands run in opposite directions to permit base pairing between them, which is essential for replication or transcription of the encoded information.

Nucleic acid sequence-based amplification, commonly referred to as NASBA, is a method in molecular biology which is used to produce multiple copies of single stranded RNA. NASBA is a two-step process that takes RNA and anneals specially designed primers, then utilizes an enzyme cocktail to amplify it.

RNA silencing or RNA interference refers to a family of gene silencing effects by which gene expression is negatively regulated by non-coding RNAs such as microRNAs. RNA silencing may also be defined as sequence-specific regulation of gene expression triggered by double-stranded RNA (dsRNA). RNA silencing mechanisms are conserved among most eukaryotes. The most common and well-studied example is RNA interference (RNAi), in which endogenously expressed microRNA (miRNA) or exogenously derived small interfering RNA (siRNA) induces the degradation of complementary messenger RNA. Other classes of small RNA have been identified, including piwi-interacting RNA (piRNA) and its subspecies repeat associated small interfering RNA (rasiRNA).

<span class="mw-page-title-main">Untranslated region</span> Non-coding regions on either end of mRNA

In molecular genetics, an untranslated region refers to either of two sections, one on each side of a coding sequence on a strand of mRNA. If it is found on the 5' side, it is called the 5' UTR, or if it is found on the 3' side, it is called the 3' UTR. mRNA is RNA that carries information from DNA to the ribosome, the site of protein synthesis (translation) within a cell. The mRNA is initially transcribed from the corresponding DNA sequence and then translated into protein. However, several regions of the mRNA are usually not translated into protein, including the 5' and 3' UTRs.

<span class="mw-page-title-main">Nucleic acid analogue</span> Compound analogous to naturally occurring RNA and DNA

Nucleic acid analogues are compounds which are analogous to naturally occurring RNA and DNA, used in medicine and in molecular biology research. Nucleic acids are chains of nucleotides, which are composed of three parts: a phosphate backbone, a pentose sugar, either ribose or deoxyribose, and one of four nucleobases. An analogue may have any of these altered. Typically the analogue nucleobases confer, among other things, different base pairing and base stacking properties. Examples include universal bases, which can pair with all four canonical bases, and phosphate-sugar backbone analogues such as PNA, which affect the properties of the chain . Nucleic acid analogues are also called xeno nucleic acids and represent one of the main pillars of xenobiology, the design of new-to-nature forms of life based on alternative biochemistries.

Adenylate-uridylate-rich elements are found in the 3' untranslated region (UTR) of many messenger RNAs (mRNAs) that code for proto-oncogenes, nuclear transcription factors, and cytokines. AREs are one of the most common determinants of RNA stability in mammalian cells. The function of AREs was originally discovered by Shaw and Kamen in 1986.

miR-122

miR-122 is a miRNA that is conserved among vertebrate species. miR-122 is not present in invertebrates, and no close paralogs of miR-122 have been detected. miR-122 is highly expressed in the liver, where it has been implicated as a regulator of fatty-acid metabolism in mouse studies. Reduced miR-122 levels are associated with hepatocellular carcinoma. miR-122 also plays an important positive role in the regulation of hepatitis C virus replication.

<span class="mw-page-title-main">RNA interference</span> Biological process of gene regulation

RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by other names, including co-suppression, post-transcriptional gene silencing (PTGS), and quelling. The detailed study of each of these seemingly different processes elucidated that the identity of these phenomena were all actually RNAi. Andrew Fire and Craig C. Mello shared the 2006 Nobel Prize in Physiology or Medicine for their work on RNAi in the nematode worm Caenorhabditis elegans, which they published in 1998. Since the discovery of RNAi and its regulatory potentials, it has become evident that RNAi has immense potential in suppression of desired genes. RNAi is now known as precise, efficient, stable and better than antisense therapy for gene suppression. Antisense RNA produced intracellularly by an expression vector may be developed and find utility as novel therapeutic agents.

<span class="mw-page-title-main">Santaris Pharma</span> Biopharmaceutical company founded in Denmark

Santaris Pharma A/S was a biopharmaceutical company founded in 2003 in Copenhagen, Denmark. The company also had a branch in San Diego, California that opened in 2009. Created by a merger between Cureon and Pantheco, Santaris developed RNA-targeted medicines using a Locked Nucleic Acid (LNA) Drug Platform and Drug Development Engine.

<small>L</small>-Ribonucleic acid aptamer RNA-like molecule

An L-ribonucleic acid aptamer is an RNA-like molecule built from L-ribose units. It is an artificial oligonucleotide named for being a mirror image of natural oligonucleotides. L-RNA aptamers are a form of aptamers. Due to their L-nucleotides, they are highly resistant to degradation by nucleases. L-RNA aptamers are considered potential drugs and are currently being tested in clinical trials.

<span class="mw-page-title-main">Xeno nucleic acid</span> Synthetic nucleic acid analogues

Xeno nucleic acids (XNA) are synthetic nucleic acid analogues that have a different backbone from the ribose and deoxyribose found in the nucleic acids of naturally occurring RNA and DNA.

Anti-miRNA oligonucleotides have many uses in cellular mechanics. These synthetically designed molecules are used to neutralize microRNA (miRNA) function in cells for desired responses. miRNA are complementary sequences to mRNA that are involved in the cleavage of RNA or the suppression of the translation. By controlling the miRNA that regulate mRNAs in cells, AMOs can be used as further regulation as well as for therapeutic treatment for certain cellular disorders. This regulation can occur through a steric blocking mechanism as well as hybridization to miRNA. These interactions, within the body between miRNA and AMOs, can be for therapeutics in disorders in which over/under expression occurs or aberrations in miRNA lead to coding issues. Some of the miRNA linked disorders that are encountered in the humans include cancers, muscular diseases, autoimmune disorders, and viruses. In order to determine the functionality of certain AMOs, the AMO/miRNA binding expression must be measured against the expressions of the isolated miRNA. The direct detection of differing levels of genetic expression allow the relationship between AMOs and miRNAs to be shown. This can be detected through luciferase activity. Understanding the miRNA sequences involved in these diseases can allow us to use anti miRNA Oligonucleotides to disrupt pathways that lead to the under/over expression of proteins of cells that can cause symptoms for these diseases.

<span class="mw-page-title-main">Zinc finger protein 226</span> Protein found in humans

Zinc finger protein 226 is a protein that in humans is encoded by the ZNF226 gene.

RNA therapeutics are a new class of medications based on ribonucleic acid (RNA). Research has been working on clinical use since the 1990s, with significant success in cancer therapy in the early 2010s. In 2020 and 2021, mRNA vaccines have been developed globally for use in combating the coronavirus disease. The Pfizer–BioNTech COVID-19 vaccine was the first mRNA vaccine approved by a medicines regulator, followed by the Moderna COVID-19 vaccine, and others.

Gapmers are short DNA antisense oligonucleotide structures with RNA-like segments on both sides of the sequence. These linear pieces of genetic information are designed to hybridize to a target piece of RNA and silence the gene through the induction of RNase H cleavage. Binding of the gapmer to the target has a higher affinity due to the modified RNA flanking regions, as well as resistance to degradation by nucleases. Gapmers are currently being developed as therapeutics for a variety of cancers, viruses, and other chronic genetic disorders.

ncRNA therapy

A majority of the human genome is made up of non-protein coding DNA. It infers that such sequences are not commonly employed to encode for a protein. However, even though these regions do not code for protein, they have other functions and carry necessary regulatory information.They can be classified based on the size of the ncRNA. Small noncoding RNA is usually categorized as being under 200 bp in length, whereas long noncoding RNA is greater than 200bp. In addition, they can be categorized by their function within the cell; Infrastructural and Regulatory ncRNAs. Infrastructural ncRNAs seem to have a housekeeping role in translation and splicing and include species such as rRNA, tRNA, snRNA.Regulatory ncRNAs are involved in the modification of other RNAs.

References

  1. 1 2 3 4 5 Titze-de-Almeida R, David C, Titze-de-Almeida SS (July 2017). "The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market". Pharmaceutical Research. 34 (7): 1339–1363. doi:10.1007/s11095-017-2134-2. PMID   28389707. S2CID   4925216.
  2. 1 2 3 "Miravirsen". PubChem .