Acidic phospholipid membranes

Acidic phospholipid membranes are biological bilayers enriched with negatively charged lipids such as phosphatidylserine (PS), phosphatidylglycerol (PG), and cardiolipin. In healthy mammalian cells, these lipids are typically sequestered in the inner leaflet of the plasma membrane, maintaining a neutral exterior surface. However, in pathological conditions like apoptosis, viral infection, or malignancy, the loss of membrane asymmetry results in the exposure of these anionic lipids on the outer surface (Birge et al., 2016). This exposure provides a unique therapeutic window, as many antimicrobial agents, such as daptomycin and polymyxins, rely on electrostatic interactions with these acidic surfaces to disrupt bacterial cell integrity (Velkov et al., 2013). In oncology, the externalization of PS in the tumor microenvironment acts as an immunosuppressive signal that can be targeted by monoclonal antibodies to restore anti-tumor immunity (Gerber et al., 2015). Furthermore, these membranes play a critical role in the assembly of coagulation factor complexes, making them central to the regulation of hemostasis. Targeting these lipid environments offers a strategy for achieving selectivity based on the biophysical properties of the membrane rather than specific protein-ligand interactions.

Other names

Anionic phospholipid membranesNegatively charged phospholipid membranesPhosphatidylserine-rich membranesPhosphatidylglycerol-containing membranesAnionic lipid bilayers

Drugs targeting acidic phospholipid membranes typically utilize cationic domains to achieve electrostatic attraction to negatively charged lipid headgroups. This binding often leads to membrane depolarization, pore formation, or the inhibition of membrane-associated enzymes. For example, daptomycin aggregates in the presence of calcium to insert into phosphatidylglycerol-rich membranes, causing rapid potassium efflux and cell death (Muller et al., 2016). In cancer, phosphatidylserine-targeting agents bind to exposed anionic lipids to induce antibody-dependent cellular cytotoxicity (ADCC) or block immunosuppressive signaling (Birge et al., 2016).