Gao Ziwei, Sasaki Jiei, Suzuki Tateki, Sando Shinsuke, Hashiguchi Takao, Morimoto Jumpei
Department of Chemistry & Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
Laboratory of Medical Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.
ChemMedChem. 2025 Sep 11;20(17):e202500532. doi: 10.1002/cmdc.202500532. Epub 2025 Jul 28.
In this study, a passively membrane-permeable short peptide inhibitor targeting the measles virus fusion protein (MeV-F) is reported. Measles virus (MeV) is highly contagious, yet no approved antiviral drugs are currently available. MeV-F plays a crucial role in viral infection, making it an attractive target for drug development. The fusion inhibitor peptide (FIP) is a well-known short peptide that binds to MeV-F and prevents its structural rearrangement. However, improving both inhibitory activity and passive membrane permeability is essential for developing orally available MeV-F inhibitors. Herein, FIP derivatives are explored through hydrogen-to-fluorine substitution and a derivative with enhanced inhibitory activity (IC = 90 nM) and passive membrane permeability (P = 1.4 × 10 cm s) was identified. This study highlights the potential of the long-studied fusion inhibitor peptide as a promising lead compound for the development of orally available drugs against measles infection.
在本研究中，报道了一种靶向麻疹病毒融合蛋白（MeV-F）的被动膜渗透性短肽抑制剂。麻疹病毒（MeV）具有高度传染性，但目前尚无获批的抗病毒药物。MeV-F在病毒感染中起关键作用，使其成为药物开发的一个有吸引力的靶点。融合抑制剂肽（FIP）是一种众所周知的短肽，它与MeV-F结合并阻止其结构重排。然而，提高抑制活性和被动膜渗透性对于开发口服可用的MeV-F抑制剂至关重要。在此，通过氢到氟的取代来探索FIP衍生物，并鉴定出一种具有增强抑制活性（IC = 90 nM）和被动膜渗透性（P = 1.4×10 cm s）的衍生物。这项研究突出了长期研究的融合抑制剂肽作为开发抗麻疹感染口服可用药物的有前景的先导化合物的潜力。
