TY - JOUR

T1 - Biostability, in vivo antiviral activity against respiratory syncytial virus, and pharmacokinetic profiles of (−)-borneol esters

AU - Sokolova, Anastasiya S.

AU - Okhina, Alina A.

AU - Shtro, Anna A.

AU - Klabukov, Artem M.

AU - Galochkina, Anastasia V.

AU - Nikolaeva, Yulia V.

AU - Petukhova, Galina D.

AU - Yarovaya, Olga I.

AU - Rogachev, Artem D.

AU - Baev, Dmitriy S.

AU - Fatyanova, Alina V.

AU - Tolstikova, Tatyana G.

AU - Salakhutdinov, Nariman F.

N1 - This work was supported by grant No. 24-13-00134 from the Russian Science Foundation. The authors would like to acknowledge the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements. The authors would like to express their gratitude to the Institute of Chemical Biology and Fundamental Medicine SB RAS for approving the experimental protocol involving human blood samples and the Institute of Cytology and Genetics SB RAS for approving the experimental protocol for pharmacokinetic assays. The English language was corrected by shevchuk-editing.com. =

PY - 2025/6/5

Y1 - 2025/6/5

N2 - 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.

AB - 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.

KW - (−)-borneol ester

KW - In vivo antiviral activity

KW - Metabolic stability

KW - Pharmacokinetics

KW - Respiratory syncytial virus inhibitor

UR - https://www.mendeley.com/catalogue/b20e32d3-05c2-36b0-ae73-ddccbec181ea/

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-105001990450&origin=inward&txGid=581fb15efe5fbda316dc5b36bc9a69ef

U2 - 10.1016/j.ejphar.2025.177567

DO - 10.1016/j.ejphar.2025.177567

M3 - Article

C2 - 40189082

VL - 996

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

M1 - 177567

ER -