| Autor: |
Elke Lipka, Aaron M. Chadderdon, Cheryl C. Harteg, Matthew K. Doherty, Eric S. Simon, John M. Domagala, Dawn M. Reyna, Kim M. Hutchings, Xinmin Gan, Andrew D. White, Caroll B. Hartline, Emma A. Harden, Kathy A. Keith, Mark N. Prichard, Scott H. James, Rhonda D. Cardin, David I. Bernstein, Jacqueline F. Spencer, Ann E. Tollefson, William S. M. Wold, Karoly Toth |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Molecular pharmaceutics. 20(1) |
| ISSN: |
1543-8392 |
| Popis: |
DNA viruses are responsible for many diseases in humans. Current treatments are often limited by toxicity, as in the case of cidofovir (CDV, Vistide), a compound used against cytomegalovirus (CMV) and adenovirus (AdV) infections. CDV is a polar molecule with poor bioavailability, and its overall clinical utility is limited by the high occurrence of acute nephrotoxicity. To circumvent these disadvantages, we designed nine CDV prodrug analogues. The prodrugs modulate the polarity of CDV with a long sulfonyl alkyl chain attached to one of the phosphono oxygens. We added capping groups to the end of the alkyl chain to minimize β-oxidation and focus the metabolism on the phosphoester hydrolysis, thereby tuning the rate of this reaction by altering the alkyl chain length. With these modifications, the prodrugs have excellent aqueous solubility, optimized metabolic stability, increased cellular permeability, and rapid intracellular conversion to the pharmacologically active diphosphate form (CDV-PP). The prodrugs exhibited significantly enhanced antiviral potency against a wide range of DNA viruses in infected human foreskin fibroblasts. Single-dose intravenous and oral pharmacokinetic experiments showed that the compounds maintained plasma and target tissue levels of CDV well above the EC |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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