Inhibitors of signal peptide peptidase (SPP) affect HSV-1 infectivity in vitro and in vivo.
Recently we have shown that the highly conserved herpes simplex virus glycoprotein K (gK) binds to signal peptide peptidase (SPP), also known as minor histocompatibility antigen H13. In this study we have demonstrated for the first time that inhibitors of SPP, such as L685,458, (Z-LL)2 ketone, aspirin, ibuprofen and DAPT, significantly reduced HSV-1 replication in tissue culture. Inhibition of SPP activity via (Z-LL)2 ketone significantly reduced viral transcripts in the nucleus of infected cells. Finally, when administered during primary infection, (Z-LL)2 ketone inhibitor reduced HSV-1 replication in the eyes of ocularly infected mice. Thus, blocking SPP activity may represent a clinically effective and expedient approach to the reduction of viral replication and the resulting pathology.
Center for Neurobiology & Vaccine Development, Ophthalmology Research, Department of Surgery, Los Angeles, CA.
Sariah J
SJ
Allen
Center for Neurobiology & Vaccine Development, Ophthalmology Research, Department of Surgery, Los Angeles, CA.
Kevin R
KR
Mott
Center for Neurobiology & Vaccine Development, Ophthalmology Research, Department of Surgery, Los Angeles, CA. Electronic address: ghiasih@cshs.org.
Homayon
H
Ghiasi
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001241:Aspirin / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002458:Cell Fractionation; D002478:Cells, Cultured; D004279:DNA, Viral / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D007052:Ibuprofen / Q000494:pharmacology; D016849:Keratitis, Herpetic / Q000517:prevention & control / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009883:Ophthalmic Solutions; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*
C415363:1, 3-di-(N-carboxybenzoyl-leucyl-leucyl)amino acetone; D002219:Carbamates; D004279:DNA, Viral; D004151:Dipeptides; D004791:Enzyme Inhibitors; C410009:L 685458; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D009883:Ophthalmic Solutions; D012333:RNA, Messenger; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase; D001241:Aspirin; D007052:Ibuprofen
(Z-LL)(2) ketone; glycoprotein K (gK); nucleus; virus replication