Expanding the toolbox of metabolically stable lipid prodrug strategies

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside and nucleotide therapeutics, small context-dependent amendments to these popular prodrug strategies can drive dramatic improvements in pharmacokinetic (PK) profiles. Herein we offer a brief overview of current prodrug strategies, as well as a case study involving the fine-tuning of lipid prodrugs of acyclic nucleoside phosphonate tenofovir (TFV), an approved nucleotide HIV reverse transcriptase inhibitor (NtRTI) and the cornerstone of combination antiretroviral therapy (cART). Installation of novel lipid terminal motifs significantly reduced fatty acid hepatic ω-oxidation while maintaining potent antiviral activity. This work contributes important insights to the expanding repertoire of lipid prodrug strategies in general, but particularly for the delivery and distribution of acyclic nucleoside phosphonates

Examples of compounds of interest as sphingoid base/ceramide analog pharmaceutical leads

<p><b>Copyright information:</b></p><p>Taken from " Biodiversity of sphingoid bases (“sphingosines”) and related amino alcohols"</p><p></p><p>Journal of Lipid Research 2008;49(8):1621-1639.</p><p>Published online 1 Aug 2008</p><p>PMCID:PMC2444003.</p><p></p

Sphingolipid Analogues Inhibit Development of Malaria Parasites

<i>Plasmodium</i>-infected erythrocytes have been shown to employ sphingolipids from both endogenous metabolism as well as existing host pools. Therapeutic agents that limit these supplies have thus emerged as intriguing, mechanistically distinct putative targets for the treatment of malaria infections. In an initial screen of our library of sphingolipid pathway modulators for efficacy against two strains of the predominant human malaria species <i>Plasmodium falciparum</i> and <i>Plasmodium knowlesi</i>, a series of orally available, 1-deoxysphingoid bases were found to possess promising in vitro antimalarial activity. To better understand the structural requirements that are necessary for this observed activity, a second series of modified analogues were prepared and evaluated. Initial pharmacokinetic assessments of key analogues were investigated to evaluate plasma and red blood cell concentrations in vivo