**A Broad-Spectrum Antiviral Peptide Blocks Infection of Viruses by Binding to Phosphatidylserine in the Viral Envelope**

**Rutger D. Luteijn 1,**†**,**‡**, Patrique Praest 1,**†**, Frank Thiele 2,**†**, Saravanan Manikam Sadasivam 3, Katrin Singethan 2, Jan W. Drijfhout 4, Christian Bach 2, Ste**ff**en Matthijn de Boer 5, Robert J. Lebbink 1, Sha Tao 6, Markus Helfer 2, Nina C. Bach 7, Ulrike Protzer 2, Ana I. Costa 1, J. Antoinette Killian 3, Ingo Drexler 6,§ and Emmanuel J. H. J. Wiertz 1,\*,§**


Received: 11 August 2020; Accepted: 27 August 2020; Published: 29 August 2020

**Abstract:** The ongoing threat of viral infections and the emergence of antiviral drug resistance warrants a ceaseless search for new antiviral compounds. Broadly-inhibiting compounds that act on elements shared by many viruses are promising antiviral candidates. Here, we identify a peptide derived from the cowpox virus protein CPXV012 as a broad-spectrum antiviral peptide. We found that CPXV012 peptide hampers infection by a multitude of clinically and economically important enveloped viruses, including poxviruses, herpes simplex virus-1, hepatitis B virus, HIV-1, and Rift Valley fever virus. Infections with non-enveloped viruses such as Coxsackie B3 virus and adenovirus are not affected. The results furthermore sugges<sup>t</sup> that viral particles are neutralized by direct interactions with CPXV012 peptide and that this cationic peptide may specifically bind to and disrupt membranes composed of the anionic phospholipid phosphatidylserine, an important component of many viral membranes. The combined results strongly sugges<sup>t</sup> that CPXV012 peptide inhibits virus infections by direct interactions with phosphatidylserine in the viral envelope. These results reiterate the potential of cationic peptides as broadly-acting virus inhibitors.

**Keywords:** antiviral peptide; enveloped viruses; membrane phosphatidylserine; envelope disruption
