Poongavanam Vasanthanathan, Peintner Stefan, Abeje Yordanos, Kölling Florian, Meibom Daniel, Erdelyi Mate, Kihlberg Jan
Department of Chemistry - BMC, Uppsala University, Box 576, 75 123 Uppsala, Sweden.
Drug Discovery Sciences, Bayer AG, 42113 Wuppertal, Germany.
ACS Med Chem Lett. 2025 Mar 17;16(4):681-687. doi: 10.1021/acsmedchemlett.5c00068. eCollection 2025 Apr 10.
The ability to adopt folded conformations that have a low solvent-accessible 3D polar surface area has been found to be important for PROTACs to display a high passive cell permeability. We have studied two VHL PROTACs that differ only by the replacement of two methylene groups in the linker by oxygen atoms but that displayed vast differences in their cell permeability. MD simulations and NMR spectroscopy revealed an unexpected, environment-dependent conformational behavior for the low-permeability PROTAC that has an alkyl linker. Hydrophobic interactions enforced extended and polar conformations for this PROTAC in nonpolar media, explaining its low cell permeability. In water, hydrophobic collapse around the linker led to folded and less polar conformations. In contrast, the highly permeable PROTAC having a PEG linker adopted conformations of similar shapes and polarities in polar and nonpolar environments.
人们发现，具备采用低溶剂可及三维极性表面积的折叠构象的能力，对于PROTAC（蛋白酶体靶向嵌合体）展现出高被动细胞通透性而言至关重要。我们研究了两种VHL PROTAC，它们仅在连接子中的两个亚甲基被氧原子取代这一点上有所不同，但在细胞通透性方面却表现出巨大差异。分子动力学模拟和核磁共振光谱揭示了具有烷基连接子的低通透性PROTAC存在一种意想不到的、依赖环境的构象行为。在非极性介质中，疏水相互作用促使该PROTAC形成伸展且极性的构象，这解释了其低细胞通透性的原因。在水中，连接子周围的疏水塌缩导致构象折叠且极性降低。相比之下，具有聚乙二醇连接子的高通透性PROTAC在极性和非极性环境中采用了形状和极性相似的构象。
