Assessment of cholesteryl ester transfer protein inhibitors for interaction with proteins involved in the immune response to infection.
The CETP inhibitor, torcetrapib, was prematurely terminated from phase 3 clinical trials due to an increase in cardiovascular and noncardiovascular mortality. Because nearly half of the latter deaths involved patients with infection, we have tested torcetrapib and other CETPIs to see if they interfere with lipopolysaccharide binding protein (LBP) or bactericidal/permeability increasing protein (BPI). No effect of these potent CETPIs on LPS binding to either protein was detected. Purified CETP itself bound weakly to LPS with a Kd >or= 25 microM compared with 0.8 and 0.5 nM for LBP and BPI, respectively, and this binding was not blocked by torcetrapib. In whole blood, LPS induced tumor necrosis factor-alpha normally in the presence of torcetrapib. Furthermore, LPS had no effect on CETP activity. We conclude that the sepsis-related mortality of the ILLUMINATE trial was unlikely due to a direct effect of torcetrapib on LBP or BPI function, nor to inhibition of an interaction of CETP with LPS. Instead, we speculate that the negative outcome seen for patients with infections might be related to the changes in plasma lipoprotein composition and metabolism, or alternatively to the known off-target effects of torcetrapib, such as aldosterone elevation, which may have aggravated the effects of sepsis.
Clark
Ronald W
RW
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. ronald.w.clark@pfizer.com
Cunningham
David
D
Cong
Yang
Y
Subashi
Timothy A
TA
Tkalcevic
George T
GT
Lloyd
David B
DB
Boyd
James G
JG
Chrunyk
Boris A
BA
Karam
George A
GA
Qiu
Xiayang
X
Wang
Ing-Kae
IK
Francone
Omar L
OL
D000209:Acute-Phase Proteins / Q000276:immunology / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000276:immunology / Q000378:metabolism; D001798:Blood Proteins / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007239:Infections / Q000276:immunology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D020349:Surface Plasmon Resonance; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011804:Quinolines; D000099231:Lipopolysaccharide-Binding Protein; C021623:bactericidal permeability increasing protein; C483909:torcetrapib