Specific inhibition of human cytomegalovirus glycoprotein B-mediated fusion by a novel thiourea small molecule.
A novel small molecule inhibitor of human cytomegalovirus (HCMV) was identified as the result of screening a chemical library by using a whole-virus infected-cell assay. Synthetic chemistry efforts yielded the analog designated CFI02, a compound whose potency had been increased about 100-fold over an initial inhibitor. The inhibitory concentration of CFI02 in various assays is in the low nanomolar range. CFI02 is a selective and potent inhibitor of HCMV; it has no activity against other CMVs, alphaherpesviruses, or unrelated viruses. Mechanism-of-action studies indicate that CFI02 acts very early in the replication cycle, inhibiting virion envelope fusion with the cell plasma membrane. Mutants resistant to CFI02 have mutations in the abundant virion envelope glycoprotein B that are sufficient to confer resistance. Taken together, the data suggest that CFI02 inhibits glycoprotein B-mediated HCMV virion fusion. Furthermore, CFI02 inhibits the cell-cell spread of HCMV. This is the first study of a potent and selective small molecule inhibitor of CMV fusion and cell-cell spread.
Jones
Thomas R
TR
Infectious Disease Section, Wyeth Research, Pearl River, New York 10965, USA. jonestr@optonline.net
Lee
Shi-Wu
SW
Johann
Stephen V
SV
Razinkov
Vladimir
V
Visalli
Robert J
RJ
Feld
Boris
B
Bloom
Jonathan D
JD
O'Connell
John
J
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000472:pathogenicity; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D014759:Viral Envelope Proteins / Q000378:metabolism* / Q000494:pharmacology; D014771:Virion / Q000378:metabolism
D000998:Antiviral Agents; C481667:CFI02; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; D013890:Thiourea