RNA drugs have imaginative space

Nature review: RNA drugs have room for imagination

Although RNA drug development has a history of 30 years, there are currently only a few RNA small molecule drugs on the global market: Vitravene (Fomivirsen), Macugen (Pegaptanib), Kynamro (Mipomersen), Defitilio (Defibrotide), Exondys 51 (eteplirsen), Spinraza (nusinersen)

On November 28th, Nature Reviews Drug Discovery published a review titled "Small molecules against RNA targets attract big backbones", which discussed the layout and discovery of RNA targets and their corresponding small molecules by large companies such as Novartis, Merck, and Pfizer. It also mentioned how start-up biotech companies such as Arrakis Therapeutics and Ribometrix collaborate with university professors to transform their achievements, and discussed the possibility and challenges of RNA target drug development from a scientific perspective. Of course, scientists believe that there is still a lot of room for imagination in the field of diseases where RNA targets can be applied.

Industry sector

Due to the short half-life and easy degradation of ribonucleic acid (RNA), as well as limitations in gene sequencing technology, RNA has not become a preferred target in drug research. With the improvement of chemical stability and the rapid development of gene sequencing, small molecule drugs targeting RNA have become a new favorite in clinical practice. Novartis, Merck, Pfizer, and some small biotech companies have begun to lay out small molecule drugs targeting RNA, hoping to unravel the mysteries of once untreatable targets and new organisms.

Novartis discovered after years of phenotype screening that the candidate drug LMI070 can increase SMN protein expression when developing a therapy for spinal muscular atrophy (SMA), the disease that Hawking suffered from. This is because the drug can bind to RNA targets. LMI070 binds to the splicing mechanism of cells and the mRNA precursor (pre mRNA) generated by the SMN2 gene, thereby regulating exon splicing and enhancing the production of functional proteins, "said Rajeev Sivasankaran, the head of rare disease development at Novartis, excitedly." We have discovered an innovative mechanism that selectively targets the splicing process with small molecules. Currently, LMI070 is undergoing phase II clinical trials for the treatment of SMA.

In addition to Novartis, Merck and Pfizer have independently discovered small molecules targeting RNA through phenotype screening, accelerating their exploration in this field. In addition, some recently established biotech companies, including Arrakis Therapeutics and Ribometrix, mainly focus on using this technology to unravel the mystery of targets that cannot be used as drugs.

Pfizer accidentally discovered a small molecule that can bind to human ribosomes. It can selectively bind to the initial polypeptide chain generated by PCSK9 transcription, thereby preventing the synthesis of PCSK9 protein.

Merck has identified over 40 different RNA targets from various biological fields and is developing different techniques to explore the RNA domain and transcriptome. They have found that small molecule lead compounds can be optimized for RNA targets almost like traditional small molecule screening projects.

Arrakis, which completed a $38 million Series A financing this year, has identified some issues during development, such as RNA targets typically not having "active sites," making it difficult to predict when small molecule RNA binding can affect biological functions, and how it regulates RNA folding, mRNA splicing, and ribosome processing. Therefore, they are using bioinformatics methods to identify RNA targets based on predicted structural features, and plan to conduct 1000 high-throughput screening experiments next year to discover candidate compounds that bind to RNA targets. However, there is currently no strong evidence to confirm the accuracy of the algorithm they used.

Scientific community

Ribosomes are molecules constructed from ribosomal RNA and proteins, which goes without saying. Ribosomal RNA is expressed in almost all cells at a very high level, and there are many cracks and pockets on the ribosome that allow small molecules to bind to it, making it relatively easy to become a target for small molecules. In theory, small molecules can be used to target multiple RNA targets, including RNA complexes, mRNA, and non coding RNA.

Although there have been research results that provide a conceptual proof for small molecule targeted RNA, this field still needs to face many unresolved issues. Many mainstream scientists are not convinced that drugs that selectively target RNA can be successful.

Dr. Matt Disney from Scripps Research Institute in Florida has discovered a small molecule called targaprimir-96, which can bind to the precursor of microRNA-96 (pri-miR-96). Pri-miR-96 generates miR-96 through RNA mutation. It is a carcinogenic miRNA, can reduce the activity of FOXO1, and plays an important role in causing breast cancer.

Targaprimir-96 inhibits the generation of miR-96 by binding to pri-miR-96, enhances FOXO1 activity, and can lead to apoptosis in tumor cells. However, Dr. Disney found that targaprimir-96 did not comply with Lipinski's rule of five, so he believes its potential drug properties are questionable.

In addition, he also found that targapermir-210, which can regulate the production of miR-210, can increase the occurrence of apoptosis in triple negative breast cancer cells through the hypoxia inducible factor (HIF) signal pathway. He is currently conducting lead optimization experiments on these compounds and collaborating with biotechnology companies to discover innovative drugs by targeting other RNAs.

The team of Dr. Amanda Hargrove, a chemist at Duke University, conducted a chemical informatics analysis of 100 ligands targeting RNA and found that the compound library used to target proteins is also applicable to targeting RNA. This means that the risk of these substances encountering problems in terms of solubility, cell permeability, and toxicity in the future will be reduced.

Scope of application

From a medical perspective, Dr. Disney firmly believes that the role of RNA in biology is infinite. In his view, almost all diseases are controlled by a certain RNA. These fields include but are not limited to tumors, neurological diseases, infectious diseases, etc.

Among them, the inability of RAS and MYC proteins in the field of tumors to become drugs has hindered the development of small molecule drugs targeting them. Researchers hope to achieve higher success rates by targeting RNA. In addition, many non coding RNAs exhibit abnormalities in tumor cells, leading to significant changes in protein expression profiles. Researchers hope to make breakthroughs in these proteins and non coding RNAs.

In the field of neurological diseases, taking Huntington's disease as an example, CAG amplification on HTT genes and mRNA can lead to the accumulation of toxic proteins. Therefore, scientists have focused on mRNA carrying trinucleotide repeat sequence amplification.

Dr. Kevin Weeks, an RNA scientist at the University of North Carolina and co-founder of Ribometrix, believes that if anyone can reliably target RNA, he will bring significant changes to healthcare.

The currently popular PD-1 drug only gained clinical recognition and large-scale application 20 years after its discovery. Although small molecule drugs that can bind to RNA have encountered setbacks, is their era also approaching?