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

Thomas J F Nieland, Jared T. Shaw, Firoz A. Jaipuri, Jay L. Duffner, Angela N. Koehler, Sotirios Banakos, Vassilis I. Zannis, Tomas Kirchhausen, Monty Krieger

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)460-472
Number of pages13
JournalBiochemistry
Volume47
Issue number1
DOIs
StatePublished - Jan 8 2008

ASJC Scopus subject areas

  • Biochemistry

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    Nieland, T. J. F., Shaw, J. T., Jaipuri, F. A., Duffner, J. L., Koehler, A. N., Banakos, S., Zannis, V. I., Kirchhausen, T., & Krieger, M. (2008). Identification of the molecular target of small molecule inhibitors of HDL receptor SR-BI activity. Biochemistry, 47(1), 460-472. https://doi.org/10.1021/bi701277x