For over three centuries, humans have been using medicinal drugs to treat symptoms of various conditions. One such condition is morning sickness in pregnant women. In the 1950s, many women were prescribed a sedative drug named thalidomide. What transpired was the most deadly man-made medical tragedy.
Figure 1: S and R enantiomers of Thalidomide (adapted from Tokunaga et al., 2018).
Thalidomide and its S and R enantiomers; compounds differing in their mirror images, shown above, were developed in 1957 in Germany by the Chemie-Grünenthal pharmaceutical company (Vargesson, 2015). Advertised as safe, highly-effective, and non-addictive, thalidomide became one of the world’s best-selling drugs, with much use being in the UK, Canada, Germany, and Australia (Vargesson, 2015b). By November 1961, practitioners worldwide began to identify birth defects resulting from thalidomide, such as shortened or absent limbs, a condition known as phocomelia (Fintel, B., Samaras, A., Carias, E., 2009). It was then withdrawn by Chemie-Grünenthal, and many countries followed suit. Since then, a generation of children and their families have lived with the lifelong effects of thalidomide, as well as many researchers determined to find out why such defects occurred.
Figure 2: Cereblon surface structure with potential thalidomide binding sites in purple boxes (PyMOL, 2021).
Thalidomide binds to cereblon, shown in Figure 2, a protein that largely governs limb outgrowth (Ito et al., 2010). This binding changes the cell’s ubiquitin ligase activity, essentially deregulating protein homeostasis (Hu and Sun, 2016). The teratogenicity, or severity of birth defects, of thalidomide appears to be based upon which form of thalidomide binds with cereblon. In 1979, Blaschke et al. stated that only the S-form was teratogenic, while the R-form was not. More recent studies have shown the two forms to interconvert in vivo due to a chiral carbon, rendering it unstable (Tokunaga et al., 2018; Vargesson, 2015). Due to this property, it is difficult to isolate one enantiomer and market it for use. Research continues to be carried out in this area (Vargesson, 2015).
After its withdrawal, thalidomide became a pertinent research topic. By 1965, researchers discovered that it was effective in the treatment of leprosy (Sheskin, 1965). It was further researched into the 1990s, with demonstrations showing anti-inflammatory properties by inhibition of TNF-ɑ (Moreira et al., 1993). Today, thalidomide has been successful in treating conditions such as HIV, lupus, Crohn’s disease, multiple myeloma, and Behcet’s disease (Vargesson, 2015). Future research into thalidomide could focus on inhibiting its binding to cereblon, potentially preventing damage to embryos.
Thalidomide affected many individuals in the 1950s and 60s, causing fetal and infantile deaths, as well as lasting repercussions in those who did survive. In the future, there is hope that it continues to affect individuals, except this time, in life-saving ways, such as through disease management. Researching and understanding the biochemistry and mechanisms of action of thalidomide are pertinent to enhancing disease treatment and preventing future tragedies.
Works cited
Blaschke G., Kraft H. P., Fickentscher K., Köhler F., 2020. [Chromatographic separation of racemic thalidomide and teratogenic activity of its enantiomers (author’s transl)]. Arzneimittel-Forschung, [online] 29(10). Available at: <https://pubmed.ncbi.nlm.nih.gov/583234/> [Accessed 30 Jan. 2021].
Fintel, B., Samaras, A., Carias, E., 2009. The Thalidomide Tragedy: Lessons for Drug Safety and Regulation | Helix Magazine. [online] Northwestern.edu. Available at: <https://helix.northwestern.edu/article/thalidomide-tragedy-lessons-drug-safety-and-regulation> [Accessed 30 Jan. 2021].
Hu, H. and Sun, S.-C., 2016. Ubiquitin signaling in immune responses. Cell Research, [online] 26(4), pp.457–483. Available at: <https://www.nature.com/articles/cr201640> [Accessed 30 Jan. 2021].
Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y. and Handa, H., 2010. Identification of a Primary Target of Thalidomide Teratogenicity. Science, [online] 327(5971), pp.1345–1350. Available at: <https://pubmed.ncbi.nlm.nih.gov/20223979/> [Accessed 30 Jan. 2021].
Moreira A.L., Sampaio E. P., Zmuidzinas A., Frindt P., Smith K. A., Kaplan G., 2012. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. The Journal of experimental medicine, [online] 177(6). Available at: <https://pubmed.ncbi.nlm.nih.gov/8496685/> [Accessed 30 Jan. 2021].
PyMOL, 2021. [computer program] Schrodinger Labs. Available at: https://pymol.org/2/ [Accessed 30 Jan. 2021].
Sheskin, J., 1965. Thalidomide in the treatment of lepra reactions. Clinical Pharmacology & Therapeutics, [online] 6(3), pp.303–306. Available at: <https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt196563303> [Accessed 30 Jan. 2021].
Tokunaga, E., Yamamoto, T., Ito, E. and Shibata, N., 2018a. Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers. Scientific Reports, [online] 8(1). Available at: <https://www.nature.com/articles/s41598-018-35457-6> [Accessed 30 Jan. 2021].
Vargesson, N., 2015. Thalidomide‐induced teratogenesis: History and mechanisms. Birth Defects Research Part C: Embryo Today: Reviews, [online] 105(2), pp.140–156. Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737249/> [Accessed 30 Jan. 2021].
Comments
5 Responses to “Turning the tide with thalidomide”
Hello!
I chose to write my blogpost on the thalidomide tragedy, with special focus on the biochemistry of thalidomide and the cereblon protein it binds to. I made use of the PyMOL software we were introduced to in one of our Drug Discovery labs, and used some of the tools to extract two of its ligands for investigation. I particularly enjoy biology and I have been excited about the content in Drug Discovery. Further, I wanted to use some of that knowledge in understanding more about thalidomide. I learned some interesting things while researching for this post, and I hope you learn something interesting as well!
Best,
Aoife H
Hello Aoife,
Your blog post was excellent. It was well-written, informative, and I appreciate the in-depth background research. I have a few suggestions that might help you in your editing process:
1. I love the figure used, but the caption makes it difficult to read the scientific names. I would suggest putting the caption into the synopsis textbox available for a caption to make the chemical structures easy to read.
2. In your third sentence in the second paragraph, I don’t think the word “associate” was the best choice as it makes the sentence sound incomplete. I would suggest saying “identify” so the sentence sounds complete and gets the message across.
This was a very nice piece, keep up the great work. Best of luck in the editing process.
Best,
Jas
Hello Jas,
Thank you for your helpful comment. I am glad you enjoyed the post. Your feedback was incredibly helpful to me in my editing process. Changing the wording definitely helps it flow much better, and defining enantiomer allows this post to reach a more diverse audience.
Thank you!
Best,
Aoife H
Hi Aoife,
Thank you for the great read! It was a super interesting topic! I have a few suggestions to help with your editing process:
1. I think there should be a citation at the end of your second paragraph.
2. Personally, I think it may be better to rephrase ” in Figure 2, above,…” I do not think you have to say “above” and instead can say something along the lines of ” Thalidomide binds to cereblon, as shown above…” or “Thalidomide binds to cereblon, as shown in figure 2…”
3. If you have room in the word count, try defining some terms such as “leprosy” and “enantiomer.”
Overall, great job! I cannot wait to read the final post.
Happy editing,
Selvi
Hello Selvi!
Thank you for reading my post! I am glad you enjoyed it. Thank you for your comment – it was quite helpful in the editing process. I have taken your feedback and moved the figure captions for both figures, allowing readers to better see them. I have also reworded the third sentence in the second paragraph; “associate” does sound quite incomplete.
Once again, thank you for your feedback!
Best,
Aoife H