A collaborative research group consisting of Professor Toshio Hakoshima of Nara Institute of Science and Technology, Professor Hiroshi Handa of Tokyo Medical University, and Professor Tetsuo Shibata of Nagoya Institute of Technology has been teratogenic in salidamide for about 40 years. We have finally succeeded in elucidating the problem related to (risk of malformation in the fetus) at the molecular level.
Thalidomide (Note) has right-handed and left-handed molecules that are enantiomerically related, but only the left-handed type is considered to be teratogenic (left-handed teratogenicity theory).However, even after taking safe right-handed thalidomide, the left-handed teratogenic theory remained questionable because it changed (racemized) into a mixture with the left-handed type in the body.
In 2010, Professor Handa and his colleagues found that the protein "cereblon" bound to thalidomide induces teratogenesis.This time, X-ray crystal structure analysis of the complex with cereblon was performed using right-handed and left-handed thalidomide.As a result, the details of how the right-handed type and the left-handed type fit in the three tryptophan pockets, which are the binding sites for cereblon, are captured by X-ray crystallography, and the left-handed type forms a more stable complex than the right-handed type. Was proved at the structural level.
Quantitative binding analysis shows that left-handed thalidomide binds about 10 times stronger than right-handed thalidomide, and that the left-handed thalidomide binds strongly to cereblon, which strongly inhibits the subsequent "self-ubiquitination". confirm.From this, it is speculated that the left-handed type induces teratogenicity, and the theory of left-handed thalidomide teratogenicity, which has been a mystery for nearly 40 years, was elucidated at the molecular level.
In the future, it is expected that a safe thalidomide-type therapeutic agent without teratogenicity will be developed, and that it will be a great stepping stone for the development of new therapeutic agents.
(Note) A drug sold as a hypnotic sedative in the 1950s.Discontinued due to teratogenic side effects.In recent years, it has been re-approved for the treatment of multiple myeloma.
Paper information:[Scientific Reports] Structural basis of thalidomide enantiomer binding to cereblon