Kim Minsoo, Kim Kwangho, Lee Jesun, Barny Lea A, Scaggs Toya D, Romaine Ian M, Jeon KyuOk, Codreanu Simona G, Sherrod Stacy D, McLean John A, Naren Anjaparavanda P, Sulikowski Gary A, Plate Lars
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37240, United States.
Program in Chemical and Physical Biology, Vanderbilt University, Nashville, Tennessee 37240-0002, United States.
ACS Chem Biol. 2025 Jul 18;20(7):1560-1573. doi: 10.1021/acschembio.5c00157. Epub 2025 Jun 20.
Cystic fibrosis (CF) pharmacological correctors improve the cystic fibrosis transmembrane conductance regulator (CFTR) protein trafficking and function. Several side effects of these correctors and adverse drug interactions have been reported, emphasizing the need to understand off-targets. We synthesized VU439, a functionalized photoaffinity ligand (PAL) of VX-445. Chemoproteomics analysis by mass spectrometry (MS) was used to identify cross-linked proteins in CF bronchial epithelial cells expressing F508del CFTR. We identified saccharopine dehydrogenase-like oxidoreductase (SCCPDH), an uncharacterized putative oxidoreductase, as a VX-445-specific off-target. We also characterized changes in the metabolomic profiles of cells overexpressing SCCPDH to determine the consequence of binding of VX-445 to SCCPDH. These data show dysregulation of amino acid metabolism and a potential inhibitory activity of VX-445 on SCCPDH. The identified off-target may explain the exacerbation of psychological symptoms observed in the clinic, thus emphasizing the need for further optimization of correctors.
囊性纤维化（CF）药物校正剂可改善囊性纤维化跨膜传导调节因子（CFTR）蛋白的转运和功能。已报道了这些校正剂的几种副作用及不良药物相互作用，这凸显了了解脱靶效应的必要性。我们合成了VU439，一种VX-445的功能化光亲和配体（PAL）。利用质谱（MS）进行的化学蛋白质组学分析，以鉴定表达F508del CFTR的CF支气管上皮细胞中的交联蛋白。我们鉴定出了一种未被表征的假定氧化还原酶——琥珀酰鸟氨酸脱氢酶样氧化还原酶（SCCPDH），作为VX-445特异性脱靶。我们还对过表达SCCPDH的细胞的代谢组学谱变化进行了表征，以确定VX-445与SCCPDH结合的后果。这些数据显示了氨基酸代谢失调以及VX-445对SCCPDH的潜在抑制活性。所鉴定出的脱靶效应可能解释了临床上观察到的心理症状加重情况，从而凸显了对校正剂进行进一步优化的必要性。
