Cell-penetrating peptide inhibits retromer-mediated human papillomavirus trafficking during virus entry.

Pengwei Zhang, Ruben Moreno, Paul F Lambert, Daniel DiMaio

Proceedings of the National Academy of Sciences of the United States of America 2020 Mar 17

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Virus replication requires critical interactions between viral proteins and cellular proteins that mediate many aspects of infection, including the transport of viral genomes to the site of replication. In human papillomavirus (HPV) infection, the cellular protein complex known as retromer binds to the L2 capsid protein and sorts incoming virions into the retrograde transport pathway for trafficking to the nucleus. Here, we show that short synthetic peptides containing the HPV16 L2 retromer-binding site and a cell-penetrating sequence enter cells, sequester retromer from the incoming HPV pseudovirus, and inhibit HPV exit from the endosome, resulting in loss of viral components from cells and in a profound, dose-dependent block to infection. The peptide also inhibits cervicovaginal HPV16 pseudovirus infection in a mouse model. These results confirm the retromer-mediated model of retrograde HPV entry and validate intracellular virus trafficking as an antiviral target. More generally, inhibiting virus replication with agents that can enter cells and disrupt essential protein-protein interactions may be applicable in broad outline to many viruses.

Citation

Pengwei Zhang, Ruben Moreno, Paul F Lambert, Daniel DiMaio. Cell-penetrating peptide inhibits retromer-mediated human papillomavirus trafficking during virus entry. Proceedings of the National Academy of Sciences of the United States of America. 2020 Mar 17;117(11):6121-6128