Sokolova Anastasiya S, Okhina Alina A, Shtro Anna A, Klabukov Artem M, Galochkina Anastasia V, Nikolaeva Yulia V, Petukhova Galina D, Yarovaya Olga I, Rogachev Artem D, Baev Dmitriy S, Fatyanova Alina V, Tolstikova Tatyana G, Salakhutdinov Nariman F
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, Akad. Lavrentiev Ave. 9, Novosibirsk, 630090, Russian Federation.
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, Akad. Lavrentiev Ave. 9, Novosibirsk, 630090, Russian Federation; Novosibirsk State University, Pirogova Str. 1, Novosibirsk, 630090, Russian Federation.
Eur J Pharmacol. 2025 Jun 5;996:177567. doi: 10.1016/j.ejphar.2025.177567. Epub 2025 Apr 4.
Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections, particularly in vulnerable populations such as infants and the elderly. In this study, we evaluated the metabolic stability, in vivo antiviral activity, and pharmacokinetic profiles of (-)-borneol esters, which were identified as potent RSV inhibitors through screening of a compound library. Two hit compounds, ST-2 and AS-645, caused a reduction in viral titers in RSV-infected mice. Intranasal administration of ST-2 proved more effective than oral one and showed enhanced antiviral activity and improved pharmacokinetic properties. Additionally, ST-2 manifested superior metabolic stability in human blood compared to murine and rat blood, suggesting that carboxylesterase activity is a key factor in the hydrolysis resistance. Given that carboxylesterase activity is higher in mouse blood than in human blood, this difference likely contributes to the observed stability of ST-2 in human blood. Molecular modeling confirmed the role of carboxylesterase in the hydrolysis of (-)-borneol esters. These findings suggest that ST-2 has potential for further development of drugs for RSV and other viral infections.
呼吸道合胞病毒（RSV）是严重下呼吸道感染的主要病因，尤其是在婴儿和老年人等易感人群中。在本研究中，我们评估了（-）-冰片酯的代谢稳定性、体内抗病毒活性和药代动力学特征，这些化合物是通过筛选化合物库而被鉴定为有效的RSV抑制剂。两种活性化合物ST-2和AS-645可使RSV感染小鼠的病毒滴度降低。经鼻给药的ST-2比口服给药更有效，且显示出增强的抗病毒活性和改善的药代动力学特性。此外，与小鼠和大鼠血液相比，ST-2在人血中表现出更高的代谢稳定性，这表明羧酸酯酶活性是抗水解的关键因素。鉴于小鼠血液中的羧酸酯酶活性高于人血，这种差异可能是导致ST-2在人血中具有稳定性的原因。分子建模证实了羧酸酯酶在（-）-冰片酯水解中的作用。这些发现表明，ST-2具有进一步开发用于RSV和其他病毒感染药物的潜力。
