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