Identification of novel allosteric nonpeptidergic inhibitors of the human cytomegalovirus-encoded chemokine receptor US28

US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection

“…A nonpeptidergic CCR1 antagonist, VUF2274 [5-(4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl)-2, 2-diphenylpentanenitrile] was identified as a full inverse agonist for PLCβ activation by US28 (Casarosa et al ., 2003b; Waldhoer et al ., 2003; Vischer et al ., 2010) (Table 2). Consequently, VUF2274 inhibited constitutive production of inositol phosphates by US28.…”

“…Especially, a glutamic acid in transmembrane 7, which is highly homologous among chemokine receptors, was found as a key residue for VUF2274 binding to US28 (Casarosa et al ., 2003a). A series of VUF2273 derivatives were synthesized to optimize their activities to inhibit CCL5 chemokine binding to US28 and production of inositol phosphates (Vischer et al ., 2010). Especially, 4-phenylpiperidine moiety within VUF2274 turned out to be essential for inverse agonism (Hulshof et al ., 2005).…”

“…Among them, methiothepin was shown to be able to block CCL5 binding to US28 with the EC 50 value of 0.4 μM (Fraile-Ramos et al ., 2001) (Table 2). A structurally related compound, octoclothepin was also reported to be an inhibitor for CCL5’s association with the US28 receptor (Vischer et al ., 2010). …”

“…A number of novel non-peptidergic inhibitors were identified as neutral antagonists or inverse agonists on US28 that allosterically inhibit chemokine binding to US28 (Vischer et al ., 2010). (4-(4-chlorophenyl)-1-(4,4-diphenylbutyl)piperidin-4-yl) methanamine was also reported as an antagonist on the human chemokine receptor CCR1 (EC 50 =3.6 μM) (Table 2) (Hulshof et al ., 2006).…”

Molecular Mechanisms Deployed by Virally Encoded G Protein–Coupled Receptors in Human Diseases

“…This molecule also inhibits 60% of the US28-mediated HIV entry. These initial studies sparked the search for new pharmacological compounds targeting vGPCRs, leading to the synthesis and pharmacological characterization of many additional novel US28 inhibitors, which hold promise for future potential clinical applications (68; 69). …”