The objective of the proposed research is to develop several new classes of pre-clinical anti-HIV drugs (Phospholipid Anti-AIDS Drugs) that have phospholipid structures in common, but which may exhibit distinct therapeutic activities. Depending upon the class, PAD are designed to act: solely as biophysical agents (e.g., HIV envelope cholesterol-depleting); principally as chemotherapeutic agents/vesicles/formulations (e.g., phospholipid conjugates of drugs already established to be active to some degree in AIDS patients); or as biophysical-acting and chemotherapeutic agents. PAD, existing mostly as vesicles/micelles, would clearly exhibit different and most likely superior pharmacokinetics, as compared with certain presently known anti-AIDS, small-molecule experimental and clinical drugs. Methods of elaboration of PAD would include natural product chemistry, semi-synthesis, and total synthesis. Preparative high resolution chromatography (liquid) would be the principal means of separation and purification of PAD and natural- product and synthetic precursor intermediates. Biochemical studies would include: determination of the effect of PAD on lipid composition of HIV and host cell membranes; exploration of the relationship between viral envelop protein structure and membrane lipid; and mechanisms of virus-target cell binding and fusion. Physical techniques commonly used for studying the properties of phospholipid and biological membranes (scanning calorimetry, nuclear magnetic resonance, spectroscopic methods, light scattering, surface tension measurements, electron microscopy) will be used to characterize, singly, and in mixtures, the physical properties of the newly synthesized and formulated lipids. The effectiveness of fluidizing agents will be monitored by fluorescence polarization in lymphocyte membranes. These physical, formulation, and biochemical approaches will be used to aid the choice of appropriate lipids and mixtures, and to guide their formulation as stable agents. Those PAD showing promising activity against HIV infectivity in culture then would be considered for toxicologic studies in mice. At this level final decision on the preclinical and possibly clinical status of PADs will be made.
