Structure-Based Optimization of Moracin M as Potent and Selective PDE4 Inhibitors with Antipsoriasis Effects DOI
Furong Zhang,

Tiansheng Zheng,

Xue Wang

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Psoriasis is a complex chronic inflammatory disease that severely affects the quality of life patients. However, current medications could only control symptoms but not cure psoriasis with unmet medical needs. Herein, structure-based optimizations natural product moracin M (IC50 2.9 μM) led to novel PDE4 inhibitor L30 greatly improved potency 8.6 nM) and remarkable selectivity across other PDEs families (>201-fold). The binding pattern revealed by cocrystal structure was different from roflumilast. Besides, effectively inhibit release cytokines chemokines in Raw264.7 HaCaT cell lines. Furthermore, topical administration exhibited significant therapeutic effects an imiquimod-induced mouse model. These findings highlighted potential as lead for treatment psoriasis.

Язык: Английский

Inhibition of GRK2-PDE4D Axis Suppresses Fibroblast-Like Synoviocytes Hyperplasia and Alleviates Experimental Arthritis DOI Creative Commons

Dafei Han,

Hanfei Sun,

Renhao Zhang

и другие.

International Journal of Biological Sciences, Год журнала: 2025, Номер 21(4), С. 1513 - 1529

Опубликована: Янв. 27, 2025

PDE4D has been reported to exhibit significantly elevated levels in the synovium of RA patients compared with OA, yet its role remains underexplored. This study aimed elucidate GRK2-PDE4D axis FLSs and explore potential as a therapeutic target for RA. Abundant expression both GRK2 was observed synovial tissues from experimental arthritis animals patients, synchronized noted patients. Global deletion Pde4d reduced disease incidence alleviated CIA mice. TNF-α upregulated expression, causing abnormal activation hyperproliferation. Inhibiting restored cAMP levels, thereby reducing hyperproliferation, migration, anti-apoptosis. Mechanistically, TNF-α-induced upregulation dependent on GRK2. Inhibition CP-25, an esterification modification paeoniflorin, proliferation, while restoring levels. Both genetic deficiency pharmacological inhibition decreased ameliorating severity animal models. is first investigate clarify that it can be regulated by These findings suggest targeting represents promising strategy

Язык: Английский

Процитировано

0
Structure-Based Optimization of Moracin M as Potent and Selective PDE4 Inhibitors with Antipsoriasis Effects DOI
Furong Zhang,

Tiansheng Zheng,

Xue Wang

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Psoriasis is a complex chronic inflammatory disease that severely affects the quality of life patients. However, current medications could only control symptoms but not cure psoriasis with unmet medical needs. Herein, structure-based optimizations natural product moracin M (IC50 2.9 μM) led to novel PDE4 inhibitor L30 greatly improved potency 8.6 nM) and remarkable selectivity across other PDEs families (>201-fold). The binding pattern revealed by cocrystal structure was different from roflumilast. Besides, effectively inhibit release cytokines chemokines in Raw264.7 HaCaT cell lines. Furthermore, topical administration exhibited significant therapeutic effects an imiquimod-induced mouse model. These findings highlighted potential as lead for treatment psoriasis.

Язык: Английский

Процитировано

0