Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

Abstract

Ion channels play key roles in almost all facets of cellular physiology and have emerged as key host cell factors for a multitude of viral infections. A catalogue of ion channel-blocking drugs have been shown to possess antiviral activity, some of which are in widespread human usage for ion channel-related diseases, highlighting new potential for drug repurposing. The emergence of ion channel-virus interactions has also revealed the intriguing possibility that channelopathies may explain some commonly observed virus induced pathologies. This field is rapidly evolving and an up-to-date summary of new discoveries can inform future perspectives. We herein discuss the role of ion channels during viral lifecycles, describe the recently identified ion channel drugs that can inhibit viral infections, and highlight the potential contribution of ion channels to virus-mediated disease.

Keywords: antivirals; channelopathies; ion channel; virus; virus–host interactions.

Figure 1

Ion channels implicated in viral entry since 2017. (A) Ifenprodil, glibenclamide, and TEA inhibit HIV through blockade of GIRK channels and K_ATP channels. (B) TEA and quinidine inhibit HAZV escape from EEs via blockade of an unknown channel. (C) Endosomal escape of SFTSV is inhibited by benidipine hydrochloride and nifedipine. (D) BUNV escape from late endosomes is inhibited by K_2P blockade. (E) EBOV escape from lysosomes is TPC2-dependent and can be blocked by verapamil, tetrandrine, nicardipine, diltiazem, and fluphenazine. (F) MERS escape from endolysosomes is prevented by tetrandrine, fangchinoline, verapamil, nimodipine, and nicardipine blockade of TPCs. (G) MCPyV and (H) SV40 ER translocation is TPC2 mediated and can be inhibited by verapamil and tetrandrine. ER translocation of MCPyV is also susceptible to blockade of K_V and T-type VGCCs by 4-AP and flunarizine respectively. (I) ER trafficking of BKPyV is CFTR dependent and susceptible to blockade by CFTR172 and glibenclamide. Key: PM: plasma membrane; EE: early endosome; LE: late endosome; EL: endolysosome. Ver: verapamil; Tet: tetrandrine; Nic: nicardipine; Dilt: diltiazem; Fluph: fluphenazine; Fang: fangchinoline; Nim: nimodipine; Nif: nifedipine; TEA: tetraethylammonium; Qd: quinidine; Ife: ifenprodil; Glib: glibenclamide; 4-AP: 4-aminopyridine.

Figure 2

Predicted mechanisms of ion channel dependence for two enveloped viruses. (A(i)) HAZV is endocytosed by an undefined mechanism. (A(ii)) Endosomal K⁺ influx triggers a conformational change in the HAZV glycoprotein spikes to a fusion-ready state. (A(iii)) Host and viral membranes fuse and RNPs are liberated into the cytosol. (B(i)) IAV is endocytosed via a clathrin-dependent or independent mechanism. (B(ii)) The virus traffics to late endosomes where the M2 viroporin is activated by acidic pH. (B(iii)) The influx of K⁺ and H⁺ destabilises matrix-RNP interactions in the core. (B(iv)) At low pH, a conformational change in HA promotes fusion and RNP release.