Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28.
G-protein coupled receptors encoded by viruses represent an unexplored class of potential drug targets. In this study, we describe the synthesis and pharmacological characterization of the first class of inverse agonists acting on the HCMV-encoded receptor US28. It is shown that replacement of the 4-hydroxy group of lead compound 1 with a methylamine group results in a significant 6-fold increase in affinity. Interestingly, increasing the rigidity of the spacer by the introduction of a double bond also leads to a significant increase in binding affinity compared to 1. These novel inverse agonists serve as valuable tools to elucidate the role of constitutive signaling in the pathogenesis of viral infection and may have therapeutic potential as leads for new antiviral drugs.
Hulshof
Janneke W
JW
Leiden/Amsterdam Center for Drug Research, LACDR, Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Vischer
Henry F
HF
Verheij
Mark H P
MH
Fratantoni
Silvina A
SA
Smit
Martine J
MJ
de Esch
Iwan J P
IJ
Leurs
Rob
R
D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003587:Cytomegalovirus / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
D019707:Receptors, Chemokine; C411191:US28 receptor, Cytomegalovirus; D014764:Viral Proteins