Bui, Thinh T. M. Ko, Hyejin Um, Soohyun Jeong, Hyeongju Kang, Suk Woo Kim, Hasun Song, Dae-geun Jung, Sang Hoon Moon, Kyuho 2025-03-22T15:30:35Z 2025-03-22T15:30:35Z 2025-03-19 2025-02 1554-8929 https://pubs.kist.re.kr/handle/201004/152048 Rho-associated protein kinase (ROCK) inhibitors are promising therapeutic agents for reducing elevated intraocular pressure in patients with glaucoma. We explored new ROCK inhibitors derived from bioactive metabolites produced by microbes, specifically cryptic metabolites from Nocardiopsis sp. MCY7, using a liquid chromatography-mass spectrometry-based chemical analysis approach integrated with metal stress-driven isolation. This strategy led to the identification of two previously undescribed linear peptides, nocarnickelamides A and B (1 and 2), and an unreported cittilin derivative, cittilin C (3). The planar structures of 1-3 were elucidated using UV spectroscopy, high-resolution mass spectrometry, and nuclear magnetic resonance. The absolute configurations of 1 and 2 were assigned using the advanced Marfey's method. Biological assays demonstrated that nocarnickelamides (1 and 2) exhibited dual inhibitory activity against ROCK1 (IC50 29.8 and 14.9 mu M, respectively) and ROCK2 (IC50 27.0 and 21.9 mu M, respectively), with molecular simulations suggesting binding to the ATP-binding site. In human trabecular meshwork cells, 2 significantly inhibited the activation of ROCK-regulated cytoskeletal contraction markers such as the myosin light chain. Nocarnickelamide B (2) is a novel dual ROCK1/2 inhibitor and a potential pharmacophore for designing new therapeutic agents to reduce intraocular pressure in glaucoma. English American Chemical Society Discovery of Dual ROCK1/2 Inhibitors from Nocardiopsis sp. under Metal Stress Article 10.1021/acschembio.4c00736 1 ACS Chemical Biology, v.20, no.2, pp.432 - 441 ACS Chemical Biology 20 2 432 441 N scie scopus 001411226000001 2-s2.0-85216844349 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article HUMAN TRABECULAR MESHWORK FORSKOLIN EYE DROPS GLAUCOMA NETARSUDIL EFFICACY SAFETY