Study of Hydrolysis Kinetics and Synthesis of Single Isomer of Phosphoramidate ProTide-Acyclovir
Issued Date
2024-01-01
Resource Type
eISSN
24701343
Scopus ID
2-s2.0-85208748520
Journal Title
ACS Omega
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Omega (2024)
Suggested Citation
Khamkhenshorngphanuch T., Mee-Udorn P., Utsintong M., Thepparit C., Srimongkolpithak N., Theeramunkong S. Study of Hydrolysis Kinetics and Synthesis of Single Isomer of Phosphoramidate ProTide-Acyclovir. ACS Omega (2024). doi:10.1021/acsomega.4c06645 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/102085
Title
Study of Hydrolysis Kinetics and Synthesis of Single Isomer of Phosphoramidate ProTide-Acyclovir
Corresponding Author(s)
Other Contributor(s)
Abstract
Acyclovir (ACV) is a vital treatment for herpes simplex (HSV) and varicella-zoster virus (VZV) infections that inhibit viral DNA polymerase. Phosphoramidate ProTides-ACV, a promising technology, circumvents the reliance on thymidine kinase (TK) for activation. Twelve novel single isomers of phosphoramidate ProTide-ACV were synthesized. Successful isomer separation was achieved, emphasizing the importance of single isomers in medical advancements. The enzymatic hydrolysis kinetics of the synthesized compounds were investigated by using carboxypeptidase Y (CPY). The results revealed a faster conversion for the isomer Rp- than for the Sp-diastereomer. Hydrolysis experiments confirmed steric hindrance effects, particularly with the tert-butyl and isopropyl groups. Molecular modeling elucidated the mechanisms of hydrolysis, supporting the results of the experiments. This research sheds light on the potential of phosphoramidate ProTides-ACV, bridging the gap in understanding their biological and metabolic properties, while supporting future investigations into anti-HSV activity. Preliminary screening revealed that three of the four single isomers demonstrated superior antiviral efficacy against wild-type HSV-1 compared to acyclovir, with isomer 24a ultimately reducing the viral yield at 200 μM. These findings emphasize the importance of isolating racemic ACV-ProTides as pure single isomers for future drug development.