Toward the identification of ZDHHC enzymes required for palmitoylation of viral protein as potential drug targets

Introduction: S-acylation is the attachment of fatty acids not only to cysteines of cellular, but also of viral proteins. The modification is often crucial for the protein´s function and hence for virus replication. Transfer of fatty acids is mediated by one or several of the 23 members of the ZDHHC family of proteins. Since their genes are linked to various human diseases, they represent drug targets.Areas covered: The authors explore whether targeting acylation of viral proteins might be a strategy to combat viral diseases. Many human pathogens contain S-acylated proteins; the ZDHHCs involved in their acylation are currently identified. Based on the 3D structure of two ZDHHCs, the regulation and the biochemistry of the palmitolyation reaction and the lipid and protein substrate specificities are discussed. The authors then speculate how ZDHHCs might recognize S-acylated membrane proteins of Influenza virus.Expert opinion: Although many viral diseases can now be treated, the available drugs bind to viral proteins that rapidly mutate and become resistant. To develop inhibitors for the genetically more stable cellular ZDHHCs, their binding sites for viral substrates need to be identified. If only a few cellular proteins are recognized by the same binding site, development of specific inhibitors may have therapeutic potential.