Double-stranded DNA viruses are responsible for many diseases in humans. While many of these exhibit long-term persistent or latent infections, some of these infections can become severe and life-threatening in immunocompromised patients. Current treatments are effective (e.g. Cidofovir, ganciclovir and foscarnet) against DNA viruses, but are limited by a number of undesired side effects. For example, Cidofovir (CDV, Vistide) is a nucleoside phosphonate that has broad spectrum antiviral activity against DNA viruses. A potent inhibitor of viral DNA polymerase, CDV is particularly active against herpesviruses and is indicated for treatment of AIDS-related cytomegalovirus (CMV) retinitis. However, like ganciclovir and foscarnet, CDV is a polar molecule with poor oral bioavailability and therefore must be administered intravenously. Moreover, its dose and overall clinical utility is limited by high occurrence of acute nephrotoxicity. As such, improved therapies are needed to treat immunocompromised patients and other high risk populations. Prodrugs, such as Brincidofovir and CDV-tyrosine-linked alkyl amides developed by our group, have been developed that conjugate CDV to a metabolically-cleavable, lipophilic carrier designed to increase cellular uptake. Intracellularly, CDV is then enzymatically released from the prodrug and then metabolized to the active viral-DNA polymerase inhibitor Cidofovir diphosphate (CDV-PP). While these analogs exhibited significant improvements in antiviral potency against numerous DNA viruses, they unfortunately exhibited high in vivo hepatic clearance. The difficulty in accounting for the several metabolites formed from these hepatic pathways poses a major development challenge and limits the amount of active metabolite reaching the virus-infected cells. To address this limitation, we propose to synthesize and evaluate new prodrugs against DNA viruses. These new analogs will be designed to maintain high antiviral activity while mitigating hepatic clearance. To achieve this, our goal outlined in this proposal, will be to evaluate metabolically-resistant chemical substituents inserted at the terminus of the lipophilic alkyl chain. In doing so, we will compare the new derivatives against CMX-001 for cell permeability and for metabolic stability in liver microsomes.
TSRL, in partnership with its academic collaborators, aims to develop alternative Cidofovir prodrugs that are designed for reduced first-pass liver metabolism, while maintaining the enhanced antiviral activity against DNA viruses that has been observed in our previous prodrugs. By reducing the abundance of metabolic byproducts produced in the liver, this breakthrough will facilitate greater delivery of active therapeutic to the target-infected cells and enable the administration of lower doses. The completion of this objective will establish a clinical development path for an antiviral therapeutic that can meet an unmet medical need in treating immunocompromised patients, and other high-risk populations, from acute DNA viral infections.
