Virus-derived peptide inhibitors of the herpes simplex virus type 1 nuclear egress complex

Abstract

Herpesviruses infect a majority of the human population, establishing lifelong latent infections for which there is no cure. Periodic viral reactivation spreads infection to new hosts while causing various disease states particularly detrimental in the immunocompromised. Efficient viral replication, and ultimately the spread of infection, is dependent on the nuclear egress complex (NEC), a conserved viral heterodimer that helps translocate mature viral capsids from the nucleus to the cytoplasm where they mature into infectious virions. Here, we have identified peptides capable of inhibiting the membrane-budding activity of the NEC in vitro. Biophysical characterization of these peptides using circular dichroism suggests that secondary structure, rather than amino acid sequence, influences the extent of inhibition. Current therapeutics that target viral DNA replication machinery are rendered ineffective by drug resistance due to viral mutations. Our results establish a basis for the development of an alternative class of inhibitors against nuclear egress, an essential step in herpesvirus replication, potentially expanding the current repertoire of available therapeutics.