## 5 Antiviral Peptides  
Viruses represent a major cause of human disease, and the emergence of viral drug resistance and epidemics induce to search for new antivirals. Natural AMPs are an interesting source of innovative antiviral agents, but more interestingly, antiviral peptides (AVPs) can be designed and optimized to block critical steps of the viral life cycle (Figure 2) [126]. In 2014, [PERSON] et al. described the AVP targeting about 60 medically significant viruses [127]. Usually, AVPs exhibit antiviral effects by inhibiting the virus directly, but their inhibition sites and the mechanism of action vary within the viral replication cycle. Most viral pathogens are present in the Emerging Infectious Diseases/Pathogens list of the US National Institute of Allergy and Infectious Diseases (NIAID), such as Small-pox virus, viral hemorrhagic fever viruses (arenaviruses, bunyaviruses, flaviviruses and filoviruses), and coronaviruses are membrane-enveloped viruses. Virus and host cell membrane fusion is necessary for virus entry and biophysical as well as biochemical features of the membrane fusion process can be common among enveloped viruses. Targeting these conserved characteristics that are necessary for membrane fusion, is emerging as a new tool for the development of broad-spectrum antivirals [128]. Figure 2: AVPs targets in viral life cycle. Depending on the type of virus and on the mode of action of the peptides, AVPs can block viral entry by binding with specific cellular receptors or interaction with viral glycoproteins, which are involved in both entry and fusion process. They may also hinder the fusion via physicochemical interaction with hydrophobic membrane–protein interfaces. AVPs can act intracellularly as well by direct influence of viral nucleic acid synthesis or blocking viral protein expression. Others modulate the antiviral immune system of the host cell by up-regulating expression of interferons and cytokines. Viral entry, which is the earliest phase of infection in the viral life cycle, is the favored target for AVPs. Most AVPs block viral entry by one of the next mechanisms: (1) interaction with heparan sulfate, (2) blocking of cell-to-cell spread, (3) interaction with specific cellular receptors, (4) interaction with viral glycoproteins, (5) membrane or viral envelope interaction [129]. Viral surface glycoproteins are involved in both the entry and penetration process and undergo conformational changes because of the interactions with the receptor proteins. Most AVP inhibit enveloped viruses' entry by physico-chemical interaction with hydrophobic membrane-protein interfaces [130]. A few examples of peptide entry inhibitors are reported. Enfuvirtide is a peptide entry inhibitor for HIV that acts by blocking the HR1 domain of the viral envelope glycoprotein 41; it was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for human use in 2003 [131]. Another class of HIV entry inhibitors, termed anchor inhibitors, target the fusion peptide [132]. The mimetic peptide, DN59, which consists of the amino acids corresponding to the amphipathic stem region of the dengue virus envelope glycoprotein was shown to interfere with the normal infective process [133]. Peptides homologous to the surface glycoproteins of HSV-1 and HSV-2 envelopes were demonstrated to be active against the herpes virus [134]. Peptide entry inhibitors were also used against other viruses, such as cytomegalovirus, influenza virus and coronaviruses [130]. ACE2-derived peptides were already used to contrast SARS-CoV infection [135], and the approaches used to synthesize peptides against coronaviruses in the past may be re-considered to design new peptides for inhibition of SARS-CoV-2 infection on the documented evidence of efficacy against SARS-CoV, MERS-CoV, SARS-related CoVs.