A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors

Protein arginine methyltransferases (PRMTs) are attractive targets for developing therapeutic agents, but selective PRMT inhibitors targeting the cofactor SAM binding site are limited. Herein, we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea, potently and selectively inhibiting PRMT3/4/5. Importantly, crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4, providing a structural basis for the selectivity. In addition, YD1113 can be modified by introducing a substrate mimic to form a "T-shaped" bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets, exhibiting potent and selective inhibition to type I PRMTs (IC50 < 5 nmol/L). In summary, we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.

Bone Marrow Mesenchymal Stem Cell Transplantation in the Repair of Rat Spinal Cord Hemisection Injury / 中国实验动物学报

objective To investigate the differentiation of bone marrow-derived mesenchymal stem cells into neurons and transplantation of the stem ceils to repair rat hemisection spinal cord injury.Methods Adherent culture was used to isolate and culture rat bone marrow mesenchymal stem cells(MSCs).The rat spinal cord homogenate supernatant was used to induce neural differentiation of the 3rd generation ceils.The nature of ceil differentiation was identified by immunohistochemistry.The rat model of hemisection spinal cord injury was prepared and BrdU was locally injected to label the induced neurons.The distribution of living cells in the injuried spinal cord was observed at 5 weeks after cell transplantation.Results MSCs were spindle and polygonal,with 1-2 nucleoli seen under the inverted microscope.After induction with spinal cord homogenate supernatant there were a number of slender cytoplasmic projections forming interwined network and showing nestin expression,therefore,indicating the neuronal nature.MSCs at 5 weeks after transplantation into the spinal cord injury were surviving and their expression of MAP-2,NF,GFAP was significantly higher than that in the control rats(P<0.05).The rat motor function was improved than before transplantation.Conclusion MSCs induced by spinal cord homogenate supernatant can be transplanted into hemisection spinal cord injury and improve the motor function of the injuries lesions.