Viral Membrane Channels: Role and Function in the Virus Life Cycle

Sze, Ching Wooen; Tan, Yee-Joo

Given that viroporins have important roles in various stages of the viral life cycle, as well as their structural differences from the human ion channels, they have become the target of interest for inhibitory drug development and antiviral therapy. The first inhibitory drug developed against M2 proton channel activity, adamantane compounds (amantadine or rimantadine), was used to treat influenza infections [188] [189] [190] . Since then, additional viroporin inhibitors have been discovered against other viruses, such as the latest compound, BIT225, targeting the Vpu of HIV-1 [75, 191] , which was initially identified from a screen for HCV p7 inhibitor [192] ; the long-alkyl-chain iminosugar (NN-DNJ) [72, 74, 139] and hexamethylene amiloride (HMA) [73, 139] against HCV p7; and pyronin B against hRSV SH protein [193] . In addition, different modes of inhibition against viroporins of other viruses have been identified from a single drug. For instance, amantadine (and its derivatives) has been shown to have an inhibitory effect not only on its intended target, M2 [189, 190] , but also on the channel conductance of HCV p7 [70, 74, 138, 155, 194] , using a different mechanism of inhibition [58] from M2 [195] . Since viroporin is an important virulence factor of the virus, viroporin drug-resistant mutants have emerged after amantadine was used as a treatment for IAV infection [189, [196] [197] [198] , further emphasizing the need to synthesize a better viroporin inhibitor. As the structure of the viroporin determines how a drug can bind and exert its inhibition, resolving the unique structure of each ion channel is of the essence in developing novel antiviral drugs. By studying the structures of the drug-resistant M2 mutants, Pielak and colleagues were able to determine the mechanisms of inhibition of the M2 inhibitors as well as the mechanism of resistance conferred by the mutations [7, 50, 51] . This information would be useful for the future development of viroporin inhibitors with improved binding and mechanism of inhibition. A recent paper by Foster et al. discussed the feasibility of using structure-guided design in search of new compounds with high binding affinity against HCV p7 [76] . Thus, solving the architecture of viroporins together with better characterization of their functional aspects will certainly aid in understanding the mechanism of action of each unique viroporin and help in developing therapeutics against these viral membrane channels. In addition to its role as an ion channel, viroporin often interacts with numerous cellular factors or signaling pathways for viral morphogenesis and assembly. Synthesizing specific inhibitors or mimetic peptides that can block such interaction will certainly be useful for fighting and developing a cure for viral infection.