You are here

Biochemistry DOI:10.1021/bi701277x

Identification of the molecular target of small molecule inhibitors of HDL receptor SR-BI activity.

Publication TypeJournal Article
Year of Publication2008
AuthorsNieland, TJF, Shaw, JT, Jaipuri, FA, Duffner, JL, Koehler, AN, Banakos, S, Zannis, VI, Kirchhausen, T, Krieger, M
Date Published2008 Jan 08
KeywordsAmines, Antigens, CD36, Biological Transport, Cell Line, Cyclopentanes, Humans, Lipid Metabolism, Lipoproteins, HDL, Liposomes, Molecular Structure, Protein Binding, Receptors, Lipoprotein, Structure-Activity Relationship, Surface Plasmon Resonance, Thiosemicarbazones

Scavenger receptor, class B, type I (SR-BI), controls high-density lipoprotein (HDL) metabolism by mediating cellular selective uptake of lipids from HDL without the concomitant degradation of the lipoprotein particle. We previously identified in a high-throughput chemical screen of intact cells five compounds (BLT-1-5) that inhibit SR-BI-dependent lipid transport from HDL, but do not block HDL binding to SR-BI on the cell surface. Although these BLTs are widely used to examine the diverse functions of SR-BI, their direct target(s), SR-BI itself or some other component of the SR-BI pathway, has not been identified. Here we show that SR-BI in the context of a membrane lipid environment is the target of BLT-1, -3, -4, and -5. The analysis using intact cells and an in vitro system of purified SR-BI reconstituted into liposomes was aided by information derived from structure-activity relationship (SAR) analysis of the most potent of these BLTs, the thiosemicarbazone BLT-1. We found that the sulfur atom of BLT-1 was crucially important for its inhibitory activity, because changing it to an oxygen atom resulted in the isostructural, but essentially inactive, semicarbazone derivative BLT-1sc. SAR analysis also established the importance of BLT-1's hydrophobic tail. BLTs and their corresponding inactive compounds can be used to explore the mechanism and function of SR-BI-mediated selective lipid uptake in diverse mammalian experimental models. Consequently, BLTs may help determine the therapeutic potential of SR-BI-targeted pharmaceutical drugs.


Alternate JournalBiochemistry
PubMed ID18067275
PubMed Central IDPMC2736594
Grant ListR01 HL052212 / HL / NHLBI NIH HHS / United States
R01 HL048739-11 / HL / NHLBI NIH HHS / United States
HL48739 / HL / NHLBI NIH HHS / United States
R01 AI063430 / AI / NIAID NIH HHS / United States
R01 AI063430-02 / AI / NIAID NIH HHS / United States
HL52212 / HL / NHLBI NIH HHS / United States
R01 HL048739 / HL / NHLBI NIH HHS / United States
AIO63430 / / PHS HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States
R01 HL052212-09 / HL / NHLBI NIH HHS / United States