The boom in small molecule RNA targeted therapies is on the way, with pharmaceutical giants around the world flocking to the market

Evrysdi's share of the spinal muscular dystrophy (SMA) treatment market has grown since August 2020, when it was approved by the FDA for listing, with cumulative sales of $8.9 million in the third quarter.
Evrysdi was developed jointly by PTC Therapeutics, the SMA Foundation and Roche, and its approval is a milestone.
Evrysdi was the first small molecule to be approved for market target RNA, a drug that works by directly targeting RNA or RNA-protein complexes, rather than just targeting disease-related proteins.
companies have also established small molecule screening platforms, but the development of this field is still in its early stages, and few other research projects have entered the clinic.
but big pharmaceutical companies such as Roche, Biogen and BMS have long flocked to establish partnerships with leading drug developers (Table 1).
biotech-pharma alliance for the development of small molecule drugs targeting RNA Source: Nature Biotechnology last April, Roche struck a massive deal with Arrakis Therapeutics covering all of Roche's research and development areas.
January 7, Roche struck a more than $1 billion strategic partnership with Ribomtrix to discover and develop small molecule therapies targeting RNA at multiple targets.
small molecule drugs have been the main drivers of innovative drugs.
of the 53 new drugs approved by the FDA in 2020, 39 are small molecule drugs, 13 of which have also been certified as breakthrough therapies.
most traditional small-molecule drugs target proteins, but only a small fraction of the entire proteomics are available, and fewer drugs are directly targeted at RNA transcripts.
but the use of small molecules to regulate RNA has great advantages, can greatly broaden the range of drug targets.
" transcription of RNA is more than translated proteins, including non-coded RNA, which could be a new target.
," explains CSO Jennifer Petter, founder and founder of Arrakis.
non-coding RNA accounts for up to 70% of the human genome, presenting a huge opportunity to develop new therapies.
: Since the birth of modern medicine, RNA has played an important role as a target for small molecule drugs.
is an amino glycoside antibiotic that can target protein synthesis that inhibits bacterial kerucleosomes.
the breakthrough discovery, it became a first-line drug for TB infection.
, TB was a terminal illness, and patients had to wait to die after infection.
that while these antibiotics can be treated as broad-spectrum antibiotics, their hybridity limits their wider use.
Existing targeted RNA therapies include small interfering RNA (siRNA) and anthogenic oligonucleotides (ASOs), which, although highly specific, still present considerable delivery challenges outside the range of a few target organs.
, for example, the antisant oligonucleotide drug Spinraza (nusinersen) approved for the treatment of SMA must be injected directly into the spine.
traditional small molecules do not have this barrier and are easily distributed in the body, but how small molecules bind and regulate RNA functions still requires insight.
proteins are made up of 20 different amino acids, while RNA consists of only four nucleotides, so they tend to look more similar than proteins.
also makes it more difficult to find drugs that bind to a single type of RNA without widespread side effects.
important thing is that the dynamic structure of RNA is constantly swaying, and it is difficult to understand its structure.
about 85% of the RNA folds into secondary and third-stage structures, and RNA with complex structures plays many important biological functions, such as gene expression regulation and catalysis, which are also the basis of the surface or pocket of the drug.
studies have shown that RNA misfolding is highly associated with disease.
RNA folding structure (source: Expansion official website) Targeting RNA is not just a simple molecular identification, first of all, RNA-targeted drugs must be able to access the structural components present in RNA targets without binding to non-targeted transcripts.
addition, compounds must interact with RNA at functional points.
structure-based targeting technology has great potential, but it also has limitations.
, for example, not all structural components are functional, so even if a small molecule that can be combined is identified, there may not be any biological effects.
Exchange Therapeutics has developed a ribonuclease targeting chimeras (RIBOTAC) to overcome these limitations, similar to PROTAC, which recruits nucleases to direct degradation of structured RNA sites.
specifically, RIBOTAC locally recruits endogenetic ribonuclease RNase L to a specific transcription, assembles to form a djumer, and the active RNase L selectively degrades RNA targets.
small molecular form similar to CRISPR and does not require transdesion of foreign guide RNA transcripts or proteins.
RIBOTAC locally eliminates abnormally functioning RNA by congesting all "players" in a thyme complex (target RNA:RIBOTAC:RNase L), using endoensitive nucleic acid processing mechanisms, rather than simply binding and suppressing it.
this technique also has a number of advantages, such as RNA degradation may be more effective, RNA enzymatic recruitment is more selective, do not need to bind functional points, etc.
source: Journalof Medicinal Chemistry in small molecule design screening, other companies have also developed techniques to overcome difficulties, such as Arrakis developed THEL-seq technology, which quickly identifies the binding location of small molecules within RNA targets and provides match selection information across multiple different RNAs.
these data complement the small molecule SAR data and RNA probe data, and can construct a computational model of RNA-match structure, so as to design a new type of RNA targeting small molecules.
there are many known and unknown challenges in the development of small molecules that target RNA.
the field is attractive, but also full of uncertainty, new drug development still has a long way to go.
but with the deepening of understanding of the dynamic structure of RNA, the increasing number of RNA associated with chronic diseases, and the addition of more research and development institutions and biotechnology companies, more "Evrysdi" is to be expected in the future.
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