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THE Thalidomide Paradox
Brief Introduction
Thalidomide was a drug responsible for limb malformations in the late 1950s when it was prescribed for pregnant women to relieve symptoms of morning sickness. Although thalidomide was banned in the mid-1960s worldwide, it recovered clinical interest because of its unique pharmacological action against leprosy, HIV and cancer. Now, it is on the market with the name THALOMID® for the treatment of patients with multiple myeloma or severe erythema nodosum leprosum.
The S and R
thalidomide
In 1979, Blaschke et al. discovered that the S and R thalidomide enantiomers display different biological properties. Only the (S)-enantiomer
is responsible for the teratogenic side effects, while no teratogenicity was
observed for the (R)-isomer in animal experiments. However, the (R)-thalidomide can undergo considerable racemization after incubation in buffer solution (τ1/2 = 12 h) as well as in serum (τ1/2 = 1 h). According to these results, the teratogenic side effects should be observed because the (S)-isomer is now present, but Blaschke did not observe these side effects.
In 2010, Handa and co-workers carried out a landmark
biological study on thalidomide by identifying cereblon (CRBN) as a
thalidomide-binding protein. They found that thalidomide induces its teratogenic effects by binding to CRBN in zebrafish and chicks. The publication of this report opened up a new era for thalidomide in science.
The biochemical studies were carried out on deuterium-substituted enantiomers of thalidomide to suppress any enantiomeric interconversion. The results revealed that the (S)-enantiomer of thalidomide displayed a 10-fold
stronger binding to CRBN and inhibition of self-ubiquitination, compared with the (R)-isomer. It means that the results reported by Blaschke are correct and that the teratogenic effects of thalidomide are exclusively induced by the (S)-enantiomer.
Thalidomide Paradox
However, one question remains regarding the clear biological
differences between the thalidomide enantiomers reported in 1979, despite the observed racemization of thalidomide. Why do animal experiments that use (R)-thalidomide not display teratogenicity if the (R)-isomer readily racemizes in vivo? This discrepancy is known as the “thalidomide paradox.”
A Good Answer
After carefully conducting studies on pure isomers and racemic samples, Shibata et al concluded that the (R)-thalidomide and (S)-thalidomide are very soluble in water (homodimers = 344.9 ug/ml). However, after racemization, the (R)and (S) thalidomide enantiomers will form a less soluble heterodimer (R-S)-thalidomide (heterodimer = 62.5 ug/ml). This heterodimer will precipitate, thus avoiding the biological effects. The (R-S)-thalidomide heterodimer has stronger hydrogen bonds (2.895Ǻ) than the R-R and S-S thalidomide homodimers (2.912Ǻ). It is also possible that the (S)-isomer that is newly formed through racemization of the (R)-isomer will not bind to CRBN because it is blocked by the formation of the strong heterodimer.
References:
Tokunaga, E.,Yamamoto, T., Ito, E. et al. Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers Sci. Rep. 8, 17131 (2018).=
Blaschke G, Kraft HP, Fickentscher K, Köhler F.
Chromatographische Racemattrennung von Thalidomid und teratogene Wirkung der Enantiomere [Chromatographic separation of racemic thalidomide and teratogenic
activity of its enantiomers (author’s transl)]. Arzneimittelforschung. 29,10:1640-2. (1979) German. PMID: 583234.
Ito, T. et al. Identification of a Primary Target of
Thalidomide Teratogenicity. Science 327, 1345–1350 (2010).
Chamberlain, P. P. et al. Structure of the human
Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat. Struct. Mol. Biol. 21, 803–809 (2014).
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Chu, Q.; Moellering, R.E.; Hilinski, G.J.; Kim,Y.W; Grossmann, T.N.; Yeh, J.T.H; Verdine G. L.
Med. Chem. Commun., 2015, 6,111
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Cell-Penetrating Peptides Derived from Animal Venoms and Toxins
An increasing number of studies have reported on the applicability of venom peptides in the diagnosis and prospective treatment of diseased processes that are dependent on selective and specific cell membrane interaction and/or receptor binding, translocation across the cell membrane (cell penetration), intracellular trafficking and subcellular localization to exert their effect.
Rádis-Baptista, G.
Cell-Penetrating Peptides Derived from Animal Venoms and Toxins.
Toxins 2021, 13, 147.
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