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

ABSTRACT

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.

KEYWORDS:

• Acylation
• acylprotein thioesterase
• drug target
• hemagglutinin
• Influenza virus
• M2
• palmitoyl acyltransferase
• protein palmitoylation
• virus
• ZDHHC

Article highlights

• S-acylation is the attachment of fatty acids, mainly palmitate, but also other acyl chains to cysteine residues of peripheral and transmembrane proteins.

• Many proteins of viral human pathogens are S-acylated; the modification is often essential for virus replication.

• S-acylation is also a crucial modification for proteins involved in the innate immune response.

• S-acylation is mediated by one or several of the 23 members of the ZDHHC family of membrane-bound acyltransferases that have distinct, but only partially overlapping substrate specificities.

• One ZDHHC is activated by palmitoylation by an upstream ZDHHC and inactivated by depalmitoylation, the responsible thioesterase is regulated by palmitoylation.

• ZDHHCs that catalyze S-acylation of viral proteins are currently identified.

• 3D structures of two ZDHHCs have been resolved that allow speculating on their lipid and protein substrate specificities.

• The development of inhibitors specific for S-acylation of viral proteins may offer potential for therapeutic applications.

This box summarizes key points contained in the article.

Acknowledgments

The article is dedicated to the memory of Michael F.G. Schmidt, who passed away this year.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Work in the authors laboratory is funded by the human frontiers science program (HFSP) and the German Research Foundation (DFG). Mohamed Rasheed Gadalla is recipient of a PhD fellowship from the DAAD (German Academic Exchange Service).