Alpiniamides E-G from the Saline Lake-Derived Streptomyces sp. QHA48 and Their Lipid Accumulation Inhibitory Activity.

Alpiniamides E-G, three previously unreported linear polyketide derivatives, along with two known compounds, were isolated from Streptomyces sp. QHA48, which was isolated from the saline lakes of Qinghai-Tibet Plateau. The structures of these compounds were determined through analysis of their spectroscopic data, as well as density functional theory prediction of NMR chemical shifts, application of the DP4+ algorithm and electronic circular dichroism (ECD) calculations. In a cell-based lipid-lowering assay, all five alpiniamides exhibited significant inhibition of lipid accumulation in HepG2 cells without inducing cytotoxic effects at a concentration of 27 µM.

Design, Synthesis, and Biological Evaluation of an Orally Bioavailable, Potent, and Selective ROCK2 Inhibitor for Psoriasis Treatment.

Psoriasis, a prevalent chronic skin disorder, remains a significant therapeutic obstacle. This study centers on rho-associated coiled-coil-containing kinase2 (ROCK2) as an advantageous target for treating psoriasis and identifies five potent and selective ROCK2 inhibitors (A31-35). Notably, A32-35 outperform KD025 in ROCK2/ROCK1 selectivity by up to 216-fold. Among these candidates, A31 emerged as an exceedingly promising molecule, showcasing remarkable inhibitory potency (IC50 = 3.7 ± 0.8 nM), 19-fold ROCK2/ROCK1 selectivity, and favorable pharmacokinetics. Insights from the binding mode study further underscored the pivotal role of interactions with Phe103 on the P-loop in determining the selectivity between ROCK1 and ROCK2. In an imiquimod-induced psoriasis-like mouse model, oral administration of A31 notably ameliorated symptoms by targeting the IL-23/Th17 axis. Based on these compelling findings, A31 was selected as a highly promising compound for further investigation as a potential treatment for psoriasis.