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Publication Abstract from PubMed

The immunoproteasome subunit LMP7 (beta5i)/LMP2 (beta1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising approach for treating autoimmune diseases. In contrast, the inhibition of the constitutive proteasome subunit beta5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over beta5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of alpha-amido boronic acids using cryo-electron microscopy (cryo-EM). The exploitation of structural differences between the proteasome subunits led to the identification of a highly selective LMP7/LMP2 dual inhibitor 19. Molecular dynamics simulation based on cryo-EM structures of the proteasome subunits complexed with 19 explained the inhibitory activity profile. In mice immunized with 4-hydroxy-3-nitrophenylacetyl conjugated to ovalbumin, results indicate that 19 is orally bioavailable and shows promise as potential treatment for autoimmune diseases.

Optimization of alpha-amido boronic acids via cryo-electron microscopy analysis: Discovery of a novel highly selective immunoproteasome subunit LMP7 (beta5i)/LMP2 (beta1i) dual inhibitor.,Arai Y, Shitama H, Yamagishi M, Ono S, Kashima A, Hiraizumi M, Tsuda N, Katayama K, Tanaka K, Koda Y, Kato S, Sakata K, Nureki O, Miyazaki H Bioorg Med Chem. 2024 Jul 15;109:117790. doi: 10.1016/j.bmc.2024.117790. Epub , 2024 Jun 12. PMID:38906067^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.