Squalamine - Mechanism of Action

Mechanism of Action

Squalamine is an amphipathic zwitterionic molecule. At physiological pH it is positively charged. Because of the stereochemistry of its steroid framework, it assumes a flat, plate-like structure. As a consequence of these physical properties, squalamine binds electrostatically to membranes made of negatively charged phospholipids(PLs). The orientation of the polar substituents on squalamine causes it to sit on the surface of the membrane to which it binds, rather than penetrate the surface. Bacteria, unlike most eukaryotic cells, display negatively charged PLs on the membrane surfaces that are exposed to the environment. Squalamine, like many of the cationic antimicrobial peptides and proteins that have been discovered to date, interacts with the plasma membranes of bacteria and disturb function; precisely how squalamine's membrane attack kills its microbial targets remains unknown. Eukaryotic cells position negatively charged PLs on the inner leaflet (the cytoplasmic face)of the plasma membrane;the outer leaflet, the surface exposed to the outside world, is populated principally by zwitterionic PLs, such as phosphatidyl choline. Why such asymmetry in the anionic phospholipid composition of the inner and outer leaflets of the plasma membrane exists is not known. Squalamine does not normally interact with the plasma membranes of normal eukaryotic cells because of the absence of negatively charged PLs on their surface. However, certain cells possess specific "transporters" that provide squalamine with an access through the membrane. Liver, capillary, and certain hematopoetic cells possess these transporters and define the pharmacology of the compound, restricting its bio-distribution to a limited numbers of tissues and organs in an animal. Once squalamine has traversed the plasma membrane, it binds electrostatically to the negatively charged cytoplasmic surface of the plasma membrane, effectively neutralizing the negative surface potential. As a consequence, proteins that are bound to that surface through electrostatic interactions are displaced. The cellular consequences of this "displacement" will vary depending upon the specific cellular context. Since proteins such as the Rho GTPases, which play a role in actin dynamics and cellular movement, are linked to the cytoplasmic surface of the plasma membrane, squalamine disrupts several Rac1-actin-dependent processes, such as growth factor dependent endothelial migration and angiogenesis. An excellent overview of squalamine's mechanism of action can be found in this recent publication.