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

Abstract

10Herpesviruses infect a majority of the human population, establishing lifelong latent infections 11 for which there is no cure. Periodic viral reactivation spreads infection to new hosts while 12 causing various disease states particularly detrimental in the immunocompromised. Efficient 13 viral replication, and ultimately the spread of infection, is dependent on the nuclear egress 14 complex (NEC), a conserved viral heterodimer that helps translocate mature viral capsids from 15 the nucleus to the cytoplasm where they mature into infectious virions. Here, we have identified 16 peptides capable of inhibiting NEC activity in vitro. Biophysical characterization of these 17 peptides using circular dichroism suggests that secondary structure, rather than amino acid 18 sequence, influences the extent of inhibition. Current therapeutics that target viral DNA 19 replication machinery are rendered ineffective by drug resistance due to viral mutations. Our 20 results establish a basis for the development of an alternative class of inhibitors against nuclear 21 egress, an essential step in herpesvirus replication, potentially expanding the current repertoire of 22 available therapeutics. 23