Serine Peptide Phosphoester Prodrugs of Cyclic Cidofovir: Synthesis, Transport, and Antiviral Activity

Abstract

Cidofovir (HPMPC, 1), a broad-spectrum antiviral agent, is currently used to treat AIDS-related human cytomegalovirus (HCMV) retinitis and has recognized therapeutic potential for orthopox virus infections, but is limited by its low oral bioavailability. Cyclic cidofovir (2) displays decreased nephrotoxicity compared to 1, while also exhibiting potent antiviral activity. Here we describe in detail the synthesis and evaluation as prodrugs of four cHPMPC dipeptide conjugates in which the free POH of 2 is esterified by the Ser side chain alcohol group of an X-L-Ser(OMe) dipeptide: 3 (X = L-Ala), 4 (X = L-Val), 5 (X = L-Leu), and 6 (X = L-Phe). Perfusion studies in the rat establish that the mesenteric permeability to 4 is more than 30-fold greater than to 1, and the bioavailability of 4 is increased 8-fold relative to 1 in an in vivo murine model. In gastrointestinal and liver homogenates, the cHPMPC prodrugs are rapidly hydrolyzed to 2. Prodrugs 3, 4, and 5 are nontoxic at 100 μM in HFF and KB cells and in cell-based plaque reduction assays had IC 50 values of 0.1-0.5 μM for HCMV and 10 μM for two orthopox viruses (vaccinia and cowpox). The enhanced transport properties of 3-6, conferred by incorporation of a toxicologically benign dipeptide moiety, and the facile cleavage of the Ser-O-P linkage suggest that these prodrugs represent a promising new approach to enhancing the bioavailability of 2.

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…An intriguing approach to cyclic cidofovir prodrugs has employed ester linkages to serine derivatives ( 57 ) [108,109]. In addition to reduction of the phosphonate charge, this approach may impart the ability for the prodrug to act as a substrate for peptide/amino acid transporters in the GI tract.…”

Transporter-Targeted Lipid Prodrugs of Cyclic Cidofovir: A Potential Approach for the Treatment of Cytomegalovirus Retinitis

“…Retinal pigment epithelium (RPE) cells display high membrane lipophilicity and tight junctions. So far, different approaches have been employed to enhance permeability of CDF such as lipid prodrugs 14 or transporter-targeted prodrugs of cCDF 1 . However, individually, these approaches have exhibited limited advantages.…”

“…1 CDF and its cyclic analogue (cCDF) are highly potent and clinically indicated in the treatment of human cytomegalovirus (hCMV) infections. 2 In addition to retinal diseases including diabetic retinopathy, glaucoma, and age-related macular degeneration, 3 CMV retinitis is another potential cause of vision impairment.…”

Cytomegalovirus antivirals and development of improved animal models

“…In a recent study, HDP-CDV treatment of congenital infection increased pup survival but did not eliminate congenital infection [53]. A group of serine peptide phosphoester prodrugs of cCDV have also been investigated which have better bioavailabilty and activity to HCMV (and poxviruses) with reduced cytotoxicity and improved activity in the rat [57-59]. Overall these recent advances are potentially encouraging for the future development of CDV derivatives.…”