The Interactions of Anti-HIV Pronucleotides with a Model Phospholipid Membrane

Pronucleotides, after entering the cell, undergo chemical or enzymatic conversion into nucleotides with a free phosphate residue, and the released nucleoside 5'-monophosphate is then phosphorylated to the biologically active form, namely nucleoside 5'-triphosphate. The active form can inhibit HIV virus replication. For the most effective therapy, it is necessary to improve the transport of prodrugs into organelles. The introduction of new functional groups into their structure increases lipophilicity and, as a result, facilitates the interaction of pronucleotide molecules with components of biological membranes. Studies of these interactions were performed using the Langmuir technique. The prototype of the biological membrane was a thin monolayer composed of phospholipid molecules, DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine). The pronucleotides were 3'-azido-3'-deoxythymidine (AZT) analogs, formed by the phosphorylation of AZT to monophosphate (AZTMP) and containing various masking moieties that could increase their lipophilicity. Our results show the influence of the pronucleotide's chemical structure on the fluidization of the model biomembrane. Changes in monolayer morphology in the presence of prodrugs were investigated by BAM microscopy. It was found that the incorporation of new groups into the structure of the drug as well as the concentration of AZT derivatives have a significant impact on the surface properties of the formed DPPC monolayer.