E5564, a
lipid A analogue, is a potent antagonist of
lipopolysaccharide (LPS). Clinically,
E5564 was developed as a possible
therapy for treatment of
sepsis and
septic shock. Surface plasmon resonance (SPR) analysis indicates that
E5564 binds to
LPS binding protein (LBP), in a manner similar to LPS. Gel-filtration radioactive chromatograms of [(14)C]-
E5564 in plasma revealed that
E5564 initially distributes to the
lipoprotein fractions, separated from
high-density lipoprotein (HDL); the bound fraction is then released and binds to HDL. Similar results were obtained by
heparin-
manganese precipitation. At doses of
E5564 relevant to its clinical use (i.e. 6 microg/ml),
antibodies against LBP did not influence either the distribution of
E5564 to non-HDL
lipoprotein fractions or the transfer of
E5564 from non-HDLs to HDL. Under these conditions, transfer of
E5564 to HDL occurs similarly in the plasma of LBP knockout (KO) mice as in the plasma from wild-type mice. In addition, plasma clearance of
E5564 in LBP KO mice is similar to that of wildtype mice. Thus, LBP binds
E5564 in a manner similar to LPS, but does not play a role in
E5564 redistribution/binding to
lipoprotein and plasma clearance.