Inhibitors of signal peptide peptidase (SPP) affect HSV-1 infectivity in vitro and in vivo

•Five different inhibitors of SPP reduced HSV-1 infectivity in vitro.•The reduced HSV-1 titer was due to blocking viral transcriptions in the nucleus.•One of the tested inhibitor also reduced HSV-1 ocular titers 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.