Source: Medical Micro
After the COVID-19 outbreak, two mRNA vaccines were quickly approved for marketing, which has attracted more attention to the development of nucleic acid drugs. In recent years, a number of nucleic acid drugs that have the potential to become blockbuster drugs have published clinical data, covering heart and metabolic diseases, liver diseases, and a variety of rare diseases. Nucleic acid drugs are expected to become the next small molecule drugs and antibody drugs. The third largest type of drug.
Nucleic acid drug category
Nucleic acid is a biological macromolecular compound formed by the polymerization of many nucleotides, and is one of the most basic substances of life. Nucleic acid drugs are a variety of oligoribonucleotides (RNA) or oligodeoxyribonucleotides (DNA) with different functions, which can directly act on disease-causing target genes or target mRNAs to treat diseases at the gene level The role of.
▲The synthesis process from DNA to RNA to protein(Image source: bing)
At present, the main nucleic acid drugs include antisense nucleic acid (ASO), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), messenger RNA (mRNA), aptamer, and ribozyme. , Antibody nucleic acid conjugated drugs (ARC), etc.
In addition to mRNA, the research and development of other nucleic acid drugs has also received more attention in recent years. In 2018, the world’s first siRNA drug (Patisiran) was approved, and it was the first nucleic acid drug to use the LNP delivery system. In recent years, the market speed of nucleic acid drugs has also accelerated. In 2018-2020 alone, there are 4 siRNA drugs, Three ASO drugs were approved (FDA and EMA). In addition, Aptamer, miRNA and other fields also have many drugs in the clinical stage.
Advantages and challenges of nucleic acid drugs
Since the 1980s, the research and development of target-based new drugs has gradually expanded, and a large number of new drugs have been discovered; traditional small-molecule chemical drugs and antibody drugs both exert pharmacological effects by binding to target proteins. The target proteins can be Enzymes, receptors, ion channels, etc.
Although small-molecule drugs have the advantages of easy production, oral administration, better pharmacokinetic properties, and easy passage through cell membranes, their development is affected by the druggability of the target (and whether the target protein has the appropriate pocket structure and size). , Depth, polarity, etc.); according to an article in Nature2018, only 3,000 of the ~20,000 proteins encoded by the human genome can be medicines, and only 700 have corresponding drugs developed (in Mainly small molecule chemicals).
The biggest advantage of nucleic acid drugs is that different drugs can be developed only by changing the base sequence of the nucleic acid. Compared with drugs that work at the traditional protein level, its development process is simple, efficient, and biologically specific; compared with genomic DNA-level treatment, nucleic acid drugs have no risk of gene integration and are more flexible at the time of treatment. The medication can be stopped when no treatment is needed.
Nucleic acid drugs have obvious advantages such as high specificity, high efficiency and long-term effect. However, with many advantages and accelerated development, nucleic acid drugs are also facing various challenges.
One is RNA modification to enhance the stability of nucleic acid drugs and reduce immunogenicity.
The second is the development of carriers to ensure the stability of RNA during the nucleic acid transfer process and nucleic acid drugs to reach target cells/target organs;
The third is the improvement of the drug delivery system. How to improve the drug delivery system to achieve the same effect with low doses.
Chemical modification of nucleic acid drugs
Exogenous nucleic acid drugs need to overcome numerous obstacles in order to enter the body to play a role. These obstacles have also caused difficulties in the development of nucleic acid drugs. However, with the development of new technologies, some of the problems have already been solved by chemical modification. And the breakthrough in delivery system technology has played a vital role in the development of nucleic acid drugs.
Chemical modification can enhance the ability of RNA drugs to resist degradation by endogenous endonucleases and exonucleases, and greatly enhance the efficacy of drugs. For siRNA drugs, chemical modification can also enhance the selectivity of their antisense strands to reduce off-target RNAi activity, and change physical and chemical properties to enhance delivery capabilities.
1. Chemical modification of sugar
In the early stage of nucleic acid drug development, many nucleic acid compounds exhibited good biological activity in vitro, but their activity in vivo was greatly reduced or completely lost. The main reason is that unmodified nucleic acids are easily broken down by enzymes or other endogenous substances in the body. The chemical modification of sugar mainly includes the modification of the 2-position hydroxyl (2’OH) of sugar to methoxy (2’OMe), fluorine (F) or (2’MOE). These modifications can successfully increase activity and selectivity, reduce off-target effects, and reduce side effects.
▲Chemical modification of sugar (picture source: reference 4)
2. Phosphoric acid skeleton modification
The most commonly used chemical modification of the phosphate backbone is phosphorothioate, that is, a non-bridging oxygen in the phosphate backbone of the nucleotide is replaced with sulfur (PS modification). The PS modification can resist the degradation of nucleases and enhance the interaction of nucleic acid drugs and plasma proteins. Binding capacity, reduce renal clearance rate and increase half-life.
▲Transformation of phosphorothioate (picture source: reference 4)
Although PS may reduce the affinity of nucleic acids and target genes, PS modification is more hydrophobic and stable, so it is still an important modification in interfering with small nucleic acids and antisense nucleic acids.
3. Modification of the five-membered ring of ribose
The modification of the five-membered ring of ribose is called the third-generation chemical modification, including bridged nucleic acid-locked nucleic acid BNAs, peptide nucleic acid PNA, phosphorodiamide morpholino oligonucleotide PMO, these modifications can further enhance nucleic acid drugs Resistance to nucleases, improved affinity and specificity, etc.
4. Other chemical modifications
In response to the different needs of nucleic acid drugs, researchers usually make modifications and transformations on bases and nucleotide chains to increase the stability of nucleic acid drugs.
So far, all RNA-targeting drugs approved by the FDA are chemically engineered RNA analogs, supporting the utility of chemical modification. Single-stranded oligonucleotides for specific chemical modification categories differ only in sequence, but they all have similar physical and chemical properties, and therefore have common pharmacokinetics and biological properties.
Delivery and administration of nucleic acid drugs
Nucleic acid drugs that rely solely on chemical modification are still easily degraded rapidly in the blood circulation, are not easy to accumulate in target tissues, and are not easy to effectively penetrate the target cell membrane to reach the site of action in the cytoplasm. Therefore, the power of the delivery system is needed.
At present, nucleic acid drug vectors are mainly divided into viral and non-viral vectors. The former includes adenovirus-associated virus (AAV), lentivirus, adenovirus and retrovirus, etc. Those include lipid carriers, vesicles and the like. From the perspective of marketed drugs, viral vectors and lipid carriers are more mature in the delivery of mRNA drugs, while small nucleic acid drugs use more carriers or technology platforms such as liposomes or GalNAc.
To date, most nucleotide therapies, including almost all approved nucleic acid drugs, have been administered locally, such as the eyes, spinal cord, and liver. Nucleotides are usually large hydrophilic polyanions, and this property means that they cannot easily pass through the plasma membrane. At the same time, oligonucleotide-based therapeutic drugs usually cannot cross the blood-brain barrier (BBB), so delivery to the central nervous system (CNS) is the next challenge for nucleic acid drugs.
It is worth noting that nucleic acid sequence design and nucleic acid modification are currently the focus of attention of researchers in the field. For chemical modification, chemically modified nucleic acid, non-natural nucleic acid sequence design or improvement, nucleic acid composition, vector construction, nucleic acid synthesis methods, etc. Technical subjects are generally patentable application subjects.
Take the new coronavirus as an example. Since its RNA is a substance that exists in natural form in nature, the “RNA of the new coronavirus” itself cannot be granted a patent. However, if a scientific researcher isolates or extracts RNA or fragments that are not known in technology from the new coronavirus for the first time and applies it (for example, transforming it into a vaccine), then both the nucleic acid and the vaccine can be granted patent rights in accordance with the law. In addition, the artificially synthesized nucleic acid molecules in the research of the new coronavirus, such as primers, probes, sgRNA, vectors, etc., are all patentable objects.
Concluding remarks
Different from the mechanism of traditional small molecule chemical drugs and antibody drugs, nucleic acid drugs can extend drug discovery to the genetic level before proteins. It is foreseeable that with the continuous expansion of indications and the continuous improvement of delivery and modification technologies, nucleic acid drugs will popularize more disease patients and truly become another class of explosive products after small molecule chemical drugs and antibody drugs.
Reference materials:
1.http://xueshu.baidu.com/usercenter/paper/show?paperid=e28268d4b63ddb3b22270ea1763b2892&site=xueshu_se
2.https://www.biospace.com/article/releases/wave-life-sciences-announces-initiation-of-dosing-in-phase-1b-2a-focus-c9-clinical-trial-of-wve- 004-in-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia/
3. Liu Xi, Sun Fang, Tao Qichang; Wisdom Master. “Analysis of the patentability of nucleic acid drugs”
4. CICC: nucleic acid drugs, the time has come
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Post time: Sep-24-2021
