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J. Biol. Chem., Vol. 278, Issue 7, 5172-5178, February 14, 2003

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Identification of the First Nonpeptidergic Inverse Agonist for a Constitutively Active Viral-encoded G Protein-coupled Receptor^*

Paola Casarosa^§, Wiro M. Menge, Rosalba Minisini^¶, Claas Otto^¶, Jane van Heteren, Aldo Jongejan, Henk Timmerman, Barbara Moepps, Frank Kirchhoff^¶, Thomas Mertens^¶§§, Martine J. Smit^**, and Rob Leurs^§§

From the  Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Chemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands and the Departments of ^¶ Virology and  Pharmacology and Toxicology, University Clinic Ulm, Albert Einstein Allee 11, D-89081 Ulm, Germany

Human cytomegalovirus (HCMV) encodes a G protein-coupled receptor (GPCR), named US28, which shows homology to chemokine receptors and binds several chemokines with high affinity. US28 induces migration of smooth muscle cells, a feature essential for the development of atherosclerosis, and may serve as a co-receptor for human immunodeficiency virus-type 1 entry into cells. Previously, we have shown that HCMV-encoded US28 displays constitutive activity, whereas its mammalian homologs do not. In this study we have identified a small nonpeptidergic molecule (VUF2274) that inhibits US28-mediated phospholipase C activation in transiently transfected COS-7 cells and in HCMV-infected fibroblasts. Moreover, VUF2274 inhibits US28-mediated HIV entry into cells. In addition, VUF2274 fully displaces radiolabeled RANTES (regulated on activation normal T cell expressed and secreted) binding at US28, apparently with a noncompetitive behavior. Different analogues of VUF2274 have been synthesized and pharmacologically characterized, to understand which features are important for its inverse agonistic activity. Finally, by means of mutational analysis of US28, we have identified a glutamic acid in transmembrane 7 (TM 7), which is highly conserved among chemokine receptors, as a critical residue for VUF2274 binding to US28. The identification of a full inverse agonist provides an important tool to investigate the relevance of US28 constitutive activity in viral pathogenesis.

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