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Drug Discovery and Repurposing

In the evolving realm of pharmaceutical therapeutics, the primary focus has centered on targeting specific proteins or enzymatic reactions. Regrettably, a substantial portion of these proteins remains “undruggable” due to conformational challenges and intricate complexities, constraining the effectiveness of current technologies. Astonishingly, up to 80% of protein targets fall within this elusive category, underscoring the pressing need for innovative techniques. Moreover, a mere 10% of human proteins are presently within the crosshairs of approved drugs, leaving an extensive array of potential therapeutic targets untapped.


A pioneering solution gaining momentum involves intervening in the protein production process before translation occurs. This strategic approach, exemplified by the recent FDA approval of Onpattro from Alnylam Pharmaceuticals—an RNAi molecule—has spurred heightened investment from pharmaceutical manufacturers.


Traditionally, drug discovery revolved around receptors and signaling proteins that regulate gene transcription. However, the intricately regulated realm of mRNA translation, encompassing RNA-binding proteins, modifications, and ribosome accessory proteins, provides a distinctive avenue for selective and tissue-specific control over protein synthesis.

Beyond RNA interference (RNAi), another frontier in RNA therapy delves into leveraging existing or small molecules ribosomes dynamics or harnessing the body’s mRNA for precise protein production. Despite challenges related to immunogenicity and degradation, companies such as Moderna Therapeutics, CureVac, and BioNTech are advancing mRNA-based drugs across diverse applications—from viral infection and cardiovascular diseases to cystic fibrosis. Targeting translation through the use of engeneered mRNA, suppressor tRNAs, tRNA-like molecules, or small molecules focusing on ribosome presents an alternative promising approach.


While these advancements highlight the promising potential of Ribosome/Translatome and RNA therapies, they are not without challenges. Current drug development techniques fall short, with over 90% of new drugs failing due to unknown disease pathology and mechanisms of action. Immagina, a Ribo-suite technology provider company, actively supports pharmaceutical developments and envisions bringing its lead compound into clinical trials. Immagina’s groundbreaking technology platform, centered on ribosome and translation, facilitates the identification of small molecules and RNA-based drugs that modulate protein synthesis, offering a high fidelity approach to address proteins deemed “undruggable.”

In the evolving realm of pharmaceutical therapeutics, the primary focus has long been targeting specific proteins or enzymatic reactions. Regrettably, ~80% of these proteins remain “undruggable” due to conformational challenges or post-translational modifications that remove or diminish the efficacy of existing treatments. Moreover, a mere 10% of human proteins are presently within the crosshairs of approved drugs, leaving an extensive array of untapped potential therapeutic targets. 

Traditionally, drug discovery revolved around receptors and signaling proteins that regulate gene transcription. Now, a pioneering solution that is gaining momentum involves intervening in the protein production process at the level of translation. This strategic approach, exemplified by the recent FDA approval of the RNA interference therapeutic drug patisiran (Onpattro, Alnylam Pharmaceuticals), has spurred heightened R&D investment in potential translation-based therapeutics.

Another frontier in RNA therapy delves into leveraging the dynamics of translation to harness the body’s own mRNA for precise protein production. Moderna Therapeutics, CureVac, and BioNTech are all advancing mRNA-based drugs across diverse applications including viral infection, cardiovascular disease, and cystic fibrosis. Targeting translation through the use of engineered mRNA, suppressor tRNAs, tRNA-like molecules, or small molecules focusing on the ribosome presents an alternative promising approach.


While these advancements highlight the promising potential of RNA-focused therapies, they are not without challenges. Current drug development techniques fall short, with over 90% of new drugs failing due to unknown mechanisms of disease pathology. 

Immagina's innovative solutions enable investigation of protein production at the RNA level, potentially leading to greater insights and opportunities for drug discovery and drug repurposing research.

References

  • Lintner, N. G. et al. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol 15, e2001882 (2017).
  • Xu, Y. et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting. Nat Med 25, 301–311 (2019).
  • Sidrauski, C., McGeachy, A. M., Ingolia, N. T. & Walter, P. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife 4, (2015).
  • Liaud, N. et al. Cellular response to small molecules that selectively stall protein synthesis by the ribosome. PLoS Genet 15, e1008057 (2019).
  • Liu, S. et al. Ribosome-targeting antibiotic control NLRP3-mediated inflammation by inhibiting mitochondrial DNA synthesis. Free Radic Biol Med 210, 75–84 (2024).
  • Sharma, J. et al. A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion. Nat Commun 12, 4358 (2021).
  • Wangen, J. R. & Green, R. Stop codon context influences genome-wide stimulation of termination codon readthrough by aminoglycosides. Elife 9, (2020).
  • Lintner, N. G. et al. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol 15, e2001882 (2017).

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References and additional resources

  1. Gebauer F, Hentze MW. Molecular mechanisms of translational control. Nature Reviews Molecular Cell Biology. 2004;5(10):827-35.
  2. Zhou T, Weems M, Wilke CO. Translationally optimal codons associate with structurally sensitive sites in proteins. Mol Biol Evol. 2009;26(7):1571-80.
  3. Pechmann S, Frydman J. Evolutionary conservation of codon optimality reveals hidden signatures of cotranslational folding. Nat Struct Mol Biol. 2013;20(2):237-43.
  4. Zhao F, Yu CH, Liu Y. Codon usage regulates protein structure and function by affecting translation elongation speed in Drosophila cells. Nucleic Acids Res. 2017;45(14):8484-92.
  5. Bazzini AA, Del Viso F, Moreno-Mateos MA, Johnstone TG, Vejnar CE, Qin Y, et al. Codon identity regulates mRNA stability and translation efficiency during the maternal-to-zygotic transition. Embo j. 2016;35(19):2087-103.
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  7. Buschauer R, Matsuo Y, Sugiyama T, Chen YH, Alhusaini N, Sweet T, et al. The Ccr4-Not complex monitors the translating ribosome for codon optimality. Science. 2020;368(6488).
  8. Radhakrishnan A, Chen YH, Martin S, Alhusaini N, Green R, Coller J. The DEAD-Box Protein Dhh1p Couples mRNA Decay and Translation by Monitoring Codon Optimality. Cell. 2016;167(1):122-32.e9. 
  9. Shu H, Donnard E, Liu B, Jung S, Wang R, Richter JD. FMRP links optimal codons to mRNA stability in neurons. Proc Natl Acad Sci U S A. 2020;117(48):30400-11.
  10. Martin S, Allan KC, Pinkard O, Sweet T, Tesar PJ, Coller J. Oligodendrocyte differentiation alters tRNA modifications and codon optimality-mediated mRNA decay. Nature Communications. 2022;13(1):5003.
  11. Jungfleisch J, Böttcher R, Talló-Parra M, Pérez-Vilaró G, Merits A, Novoa EM, et al. CHIKV infection reprograms codon optimality to favor viral RNA translation by altering the tRNA epitranscriptome. Nature Communications. 2022;13(1):4725. 
  12. https://www.science.org/doi/full/10.1126/sciadv.abj3967
  13. https://www.nature.com/articles/s41467-022-32791-2
  14. https://elifesciences.org/articles/52629
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