Design and Development of Drugs that Target Virus Ion Channels

Abstract

Virus ion channels are small (3-15 kD) peptides that aggregate to form ion channels that are important for viral infection1. As viruses continue to pose a major worldwide health problem, these ion channels represent an exciting new target for therapeutic intervention. Viral ion channels that have been previously identified include Vpu of the human immunodeficiency virus (HIV) and P7 of Hepatitis C however it is the M2 influenza A protein that represents the best exploited ion channel drug target so far.The proton-selective M2 ion channel is the target of the adamantane family of drug inhibitors. Use of the two most common adamantane inhibitors, amantadine and rimantadine have declined steadily over recent years due to the emergence of adamantane-resistant flu strains. We have conducted a series of surface plasmon resonance experiments designed to measure the affinity between several ion channel inhibitors and M22. By examining drug binding to a number of mutant M2 constructs (derived from adamantane-resistant strains), it was possible to establish the location of the drug binding sites and to rationalise the effect on drug binding of specific mutant residues. In light of these results, the prospect for future development of a new generation of M2 inhibitors will be discussed. Moreover, we explore the possibility of expanding this field of research to incorporate ion channel proteins from other viruses.1. Gonzalez, M and Carrasco, L (2003). FEBS Lett. (2003) 552(1):28-34.2. Rosenberg, M and Casarotto, M (2010) PNAS 107(31):13866-71.