*4.1. Poxviruses*

The CPXV012 peptide was able to inhibit infection with different orthopoxviruses (MVA, VACV, and CPXV) in several cell lines, using various detection methods. Notably, early gene expression, which starts immediately after virus entry, was highly reduced and indicates a block at the entry step. Viral particles of the poxviridae family adopt distinct structures and composition of the outer membrane, such as mature virions (MVs, also named IMVs, intracellular mature virus) [52]. MVs represent the majority of infectious progeny; they are very stable and largely responsible for viral spread. In viral preparations, MVs are the most abundant virion form. Importantly, membranes of MVs have been shown to contain large amounts of PS that is essential for entry [47,53]. We found that CPXV012 peptide binds to PS and thus likely mediates its inhibitory effect on poxvirus infection by interacting with PS in the viral membrane. This was confirmed by the observation that pretreating virions with CPXV012 peptide effectively blocked infection.