**7. Conclusions**

The journey of viral infections is also a procedure during which a virus grabs the host intracellular calcium signaling system and homeostasis to benefit its own lifecycle. The disturbance of the host Ca2+ system by virus may suppress T-cell responsiveness, antiapoptotic, and other protentional functions. In this review, we summarized the calcium permeable channels and calcium pumps located on host cell membranes that may be potential therapeutic targets for viral infections (Table 1). However, the calcium channel family is continuously being refreshed with the discovery of new members, and the effect of viruses on the host intracellular calcium environment is not often achieved through a single pathway; it is more complicated. Both upstream messengers and downstream Ca2+ binding proteins are targets for pharmacological intervention. Thus, explicating the entire picture of all aspects of the calcium–virus interplay at the molecular level will be a challenge in the future.

The prevention of and therapeutic efforts against virus infections are often challenged by the high mutation rates of viral proteins. However, those host calcium apparatus proteins required by viral replication and transmission are highly conserved, essentially immutable, and thus are potentially an Achilles' heel of virus infection. As described above, almost all the calcium permeable channels or calcium pumps are possible attack targets of viruses and customized host intracellular calcium signaling via effects on these channel proteins. Targeting those host cellular proteins required by virus infection may be one treatment strategy with therapeutic potential, which may avoid or delay the development of resistance. The identified calcium-permeable proteins discussed above offer suitable target proteins for inhibiting virus infection. VGCCs and NMDA receptors are two of most well studied targets because of the availability of specific channel antagonists. Moreover, some of those compounds are FDA-approved drugs with clinical application. For example, verapamil, amlodipine, verapamil, and diltiazem, which are widely used to treat cardiovascular disease, have shown inhibition for various virus infection. Memantine, which is an FDA-approved Alzheimer's drug, reduces neurological complications associated with Zika virus infection. Obviously, this direction depends on the identification of selective and potent small molecule modulators of calcium channels. Currently, aside from some blockers for VGCCs and the NMDA receptor, almost no other channel modulators can be used in clinics, although important progress has been made in recent years toward high quality and widely available channel modulators. Furthermore, modulators should be generated with properties that make them suitable for in vivo use. This review outlines promising progress made with the potentiation for a host cell calcium channels modulator to become an antiviral drug. We believe that modulators for host calcium channels are the pots of gold for antiviral drug development.


Two-pore channels (TPCs), Stromal interaction molecule 1 (STIM1), Transient receptor potential vanilloid 4 (TRPV4), N-methyl-D-aspartate receptor (NMDAR), IP3 receptor (IP3R),

Secretory pathway Ca2+-ATPase (SPCA1). DEAD-box RNA helicase (DDX3X), Endoplasmic reticulum (ER).

**Table 1.** Calcium channels/pumps utilized by a virus.

**Author Contributions:** X.C. and W.Z. conceived this article; X.C. and R.C. wrote the original draft and prepared figures; R.C. and W.Z. edited and reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was funded by the National Natural Science Foundation of China, gran<sup>t</sup> numbers 81773631 and 81900402), National Science and Technology Major Projects, gran<sup>t</sup> number 2018ZX09711003 and Fundamental Research Funds for the Central Universities gran<sup>t</sup> number G2019KY0501.

**Conflicts of Interest:** The authors declare no conflict of interest.
