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Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir.

ABSTRACT: We report the synthesis and biological evaluation of Ala-(Val-)l-Ser-CO(2)R prodrugs of 1, where a dipeptide promoiety is conjugated to the P(OH)(2) group of cidofovir (1) via esterification by the Ser side chain hydroxyl group and an ethyl group (4 and 5) or alone (6 and 7). In a murine model, oral administration of 4 or 5 did not significantly increase total cidofovir species in the plasma compared to 1 or 2, but 7 resulted in a 15-fold increase in a rat model and had an in vitro EC(50) value against human cytomegalovirus comparable to 1. Neither 6 nor 7 exhibited toxicity up to 100 ?M in KB or HFF cells.

SUBMITTER: Peterson LW

PROVIDER: S-EPMC3115518 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir.

Peterson Larryn W LW Kim Jae-Seung JS Kijek Paul P Mitchell Stefanie S Hilfinger John J Breitenbach Julie J Borysko Kathy K Drach John C JC Kashemirov Boris A BA McKenna Charles E CE

Bioorganic & medicinal chemistry letters 20110503 13

We report the synthesis and biological evaluation of Ala-(Val-)l-Ser-CO(2)R prodrugs of 1, where a dipeptide promoiety is conjugated to the P(OH)(2) group of cidofovir (1) via esterification by the Ser side chain hydroxyl group and an ethyl group (4 and 5) or alone (6 and 7). In a murine model, oral administration of 4 or 5 did not significantly increase total cidofovir species in the plasma compared to 1 or 2, but 7 resulted in a 15-fold increase in a rat model and had an in vitro EC(50) value ...[more]

PMID: 21641218

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Project description:The double-stranded DNA (dsDNA) viruses represented by adenovirus and monkeypox virus, have attracted widespread attention due to their high infectivity. In 2022, the global outbreak of mpox (or monkeypox) has led to the declaration of a Public Health Emergency of International Concern. However, to date therapeutics approved for dsDNA virus infections remain limited and there are still no available treatments for some of these diseases. The development of new therapies for treating dsDNA infection is in urgent need. In this study, we designed and synthesized a series of novel disulfide-incorporated lipid conjugates of cidofovir (CDV) as potential candidates against dsDNA viruses including vaccinia virus (VACV) and adenovirus (AdV) 5. The structure-activity relationship analyses revealed that the optimum linker moiety was C2H4 and the optimum aliphatic chain length was 18 or 20 atoms. Among the synthesized conjugates, 1c exhibited more potency against VACV (IC50 = 0.0960 μM in Vero cells; IC50 = 0.0790 μM in A549 cells) and AdV5 (IC50 = 0.1572 μM in A549 cells) than brincidofovir (BCV). The transmission electron microscopy (TEM) images revealed that the conjugates could form micelles in phosphate buffer. The stability studies in the GSH environment demonstrated that the formation of micelles in phosphate buffer might protect the disulfide bond from glutathione (GSH) reduction. The dominant means of the synthetic conjugates to liberate the parent drug CDV was by enzymatic hydrolysis. Furthermore, the synthetic conjugates remained sufficiently stable in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and pooled human plasma, which indicated the possibility for oral administration. These results indicated 1c may be a broad-spectrum antiviral candidate against dsDNA viruses with potential oral administration. Moreover, modification of the aliphatic chain attached to the nucleoside phosphonate group was involved as an efficient prodrug strategy for the development of potent antiviral candidates.

Dataset Information

Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir.

Publications

Synthesis, transport and antiviral activity of Ala-Ser and Val-Ser prodrugs of cidofovir.

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