The in vitro activity of Cidofovir and Leflunomide is modest, and the selectivity index is low. There is a need to develop more effective and less toxic anti-BK virus drugs for clinical use.

Polyomavirus BK is a significant pathogen in transplant recipients, but no effective antiviral therapy is available. We show that cidofovir can inhibit BK virus replication in vitro. Esterification of cidofovir with hexadecyloxypropyl, octadecyloxyethyl, and oleyloxyethyl groups results in up to a 3-log lowering of the 50% effective concentration and an increased selectivity index.

Polyomavirus BK is an important pathogen in transplant recipients with no effective therapy. This study demonstrates that alkoxyalkyl esters of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and fatty acid derivatives of 9-[2-(phosphonomethyoxy)ethyl]adenine (P393 and P405) are potent and selective inhibitors of BK virus replication in vitro, with a 50% effective concentration in the micromolar-tonanomolar range.Polyomaviruses are widely latent DNA viruses, of which the most important species is BK virus (BKV). BKV is reactivated in 20 to 60% of renal transplant recipients, and nephropathy develops in up to 10% of them. BKV is also associated with hemorrhagic cystitis in up to 60% of bone marrow transplant patients (19,26). No effective antiviral therapies are available. Although some medical centers have empirically used leflunomide and cidofovir, no proven clinical benefit has resulted (10,23,25).We investigated the antiviral activities of several nucleoside analogs by using the BKV Gardner strain (ATCC VR837) grown in log-phase WI-38 cells (ATCC CCL-75) (7) in a 7-day quantitative PCR assay of viral replication. Toxicity was evaluated by the conventional neutral red assay and by quantifying the housekeeping gene for aspartoacylase. The technical details of these methods have been published previously (6,19,20). Selected chemical structures are depicted in Fig. 1 and 2, and the results of testing are summarized in Table 1.Acyclic nucleoside phosphonates were tested because this class of compounds encompasses several clinically useful antiviral agents. In our system, 9-[2-(phosphonomethyoxy)-ethyl]adenine (PMEA) showed no significant activity (selectivity index [SI] ϭ 1.3), confirming and extending prior work done with mouse polyomavirus (1). The prodrug form PMEA dipivoxil was approximately 2 logs more potent but showed only a marginal increase in selectivity (SI ϭ 5.74). However, fatty acid derivatives of PMEA, namely, P393 and P405 (Fig. 1), showed striking activity. P393 exhibited a 50% cytotoxic concentration (CC 50 ), a 50% effective concentration (EC 50 ), and an SI of 165.3 Ϯ 11.6 M, 1.0 Ϯ 0.31 M, and 58.9, respectively. P405 had a comparable EC 50 (2.3 Ϯ 0.03 M), but the CC 50 was Ͼ100 M and Ͼ200 M in the first two experiments. By repeating the experiment in a concentration range of 100 to 1,000 M, a more precise value of 528.6 M was obtained and this generated an SI of 232.8. The mechanism by which fatty acid side chains enhance the efficacy of the parent compound was not determined. The possibility of increased transport into infected cells was considered, but one might have expected this to have resulted in lowering of the CC 50 , and this was not observed. Notably, while PMEA dipivoxil also increased cell permeability compared to the parent compound, as reflected by a lower EC 50 , it did not have the same selectivity as the PMEA derivatives.(S)-9-(3-Hydroxy-2-phosphonylmethoxypropyl)-adenine [(S)-HPMPA] is the adenine analog of the broad-spectrum compound cidofovir. (S)-HPMPA is a broad-spectr...

BK virus is an important pathogen in kidney transplant recipients. In vitro studies demonstrated slight antiviral activity for chloroquine and nystatin. A sialic acid derivative, BTB11968, was identified as a lead compound for further development.