SARS-CoV-2 Drug Discovery: Targeting Viral Ion Channels
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Ion channels are well validated drug discovery targets based on their widespread distribution in the human body and involvement in many critical activities within the brain, heart, smooth muscle and endocrine organs. Additional validation is provided by channelopathy mutations associated with common diseases such as epilepsy and cardiac arrhythmia as well as in many rare disease patient populations.1 In addition, ion channels are expressed in human disease vectors (e.g. malaria parasite) and infective agents such as bacteria and viruses, presenting new areas where ion channel drug discovery can deliver novel therapeutic approaches and agents to improve human health.2 The SARS-CoV-2 virus is a very topical example of where this second approach can be applied to the creation of novel therapeutics, as the sequencing of the COVID-19 genome in early 2020 revealed the presence of several envelope E protein and putative ion channel genes.3 Numerous academic groups have begun to target COVID-19 viral ion channels (viroporins) during the course of the pandemic to understand their structure–function and utility as anti-viral drug substrates, including a group from Massachusetts Institute of Technology (MIT) that recently published the NMR solution structure of the E ion channel protein that they used for initial ligand screening.4
This study from MIT illustrates some of the challenges of modern ion channel drug discovery techniques, which can affect the identification of novel ligands for both human and viral ion channel proteins. Firstly, having a novel gene sequence may allow homology mapping onto the structure of related and better-characterized protein structures, but brings with it issues of evolutionary and functional diversification. For example, although the influenza virus M2 cation channel has been studied for many years,2 the MIT group found that the COVID-19 coronavirus E protein has a very different structure once expressed in a biological membrane, and thus inferences from homology modeling may be misleading. Secondly, it is now possible to obtain high-fidelity protein structures, including that of SARS-CoV-2 viroporins,5 and use sophisticated computing software to implement structure-based drug design approaches whereby known drug structures are virtually bound to the target of interest. The MIT study provides an example of the risk in using such an approach for a novel protein, as the prediction that anandamide, a relatively potent inhibitor of the ‘flu M2 cation channel, could also efficaciously inhibit the COVID-19 ion channel was not borne out as only weak micromolar affinity was seen in their NMR binding experiments.
This recent study does however point the way towards discovering effective inhibitors of SARS-CoV-2 viral ion channels with therapeutic potential. The MIT group managed to express a viral channel protein in lipid membranes, which will allow for functional screening of modulators that can affect channel biophysics and ionic flux through the pore. It is possible to screen for viroporin modulators using functional bacterial and yeast assays,6 but it is unclear at this stage if these hit compounds will deliver antiviral activity in human cells and patients. Nevertheless, identification of selective ligands will enable testing the hypothesis, that modulating SARS-CoV-2 viroporin activity can limit COVID-19 virus infectivity or replication in intact cellular systems, as shown for SARS CoV E protein. This COVID-19 viroporin target and mechanistic validation should also be done genetically, using RNA knockdown or CRISPR editing in human respiratory cell lines and patient lung samples, as it was for the original SARS viroporin. Finally, screening approved clinical drugs against COVID-19 viroporins could rapidly identify drug repurposing hits that can be used on patients, especially those not suited to vaccination owing to compromised immune systems.
The ultimate hope is that academic and industry groups can identify repurposed and novel drugs to inhibit a range of viral ion channels and thus offer an alternative strategy to treat both current endemic viral diseases as well as pandemic infections of the future.
1. Imbrici P, Liantonio, A, Camerino GM, et al. Therapeutic approaches to genetic ion channelopathies and perspectives in drug discovery. Front. Pharmacol. 2016. doi:10.3389/fphar.2016.00121
2. Charlton FW, Pearson HM, Hover S, et al. Ion channels as therapeutic targets for viral infections: Further discoveries and future perspectives. Viruses. 2020;12(8):844. doi:10.3390/v12080844
3. McClenaghan C, Hanson A, Lee S-J, Nichols CG. Coronavirus proteins as ion channels: Current and potential research. Front. Immunol. 2020. doi:10.3389/fimmu.2020.573339
4. Mandala VS, McKay MJ, Shcherbakov AA, et al. Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers. Nat Struct Mol Biol. 2020;27:1202-1208. doi:10.1038/s41594-020-00536-8
5. Kern DM, Sorum B, Hoel CM, et al. Cryo-EM structure of the SARS-CoV-2 3a ion channel in lipid nanodiscs. bioRxiv. 2020. doi:10.1101/2020.06.17.156554 (preprint)
6. Tomar and Arkin. SARS-CoV-2 E protein is a potential ion channel that can be inhibited by Gliclazide and Memantine. Biochem Biophys Res Commun. 2020;530(1):10-14. doi:10.1016/j.bbrc.2020.05.206