**19. Conclusions**

The novel SARS-CoV-2 virus is projected to remain a threat to global public health for at least another two years since its first occurrence in late 2019. While vaccine and antiviral research is underway, the rapid spread and fatality due to the virus indicates that pharmaceuticals will not be enough to stop this disease. Global health policy and coordination between local and national governments will be essential in order to slow the spread. The effectivity of a future vaccine must be coupled with proper social distancing, public health practices and education [394]. In this review, we detail the extensive coronavirus genome, its proteins, and their roles in viral replication and pathogenesis. The virus is notoriously capable of evading host innate immune systems, while still inducing severe disease and inflammation. Long term adaptive immunity against the virus remains in question, placing a larger pressure on effective vaccine research [395]. Optimistically, there are many targets within the coronavirus proteome, especially in the transmembrane proteins, to counteract the severe inflammation in the interest of antivirals detailed in this review. Research efforts over the past 20 years have revealed several targetable sites in most CoV proteins with identified immunoregulatory functions.

Novel human infecting pathogenic viruses resulting from zoonotic jumping are not uncommon as virologists and epidemiologists fervently study pig and bird influenzas that may have jumped to humans. Other viruses that have caused widespread epidemics that sparked a wave of research into antivirals are HIV and Ebola [396,397]. Until recently, coronaviruses have gone largely underrepresented as growing threats to civilization, despite being responsible for two epidemics in China 2003 (SARS) and the Middle East 2012-present (MERS). Additionally, minor outbreaks of HKU1-CoV occurred in Hong Kong and the USA causing mild to severe pneumonia [398,399]. Coronaviruses are also a costly agricultural nuisance with Porcine Epidemic Diarrhea Virus and Infectious Bovine Virus, largely affecting pork and cattle supply and economy, respectively [400,401]. Despite this history, antivirals against CoVs are virtually nonexistent, making humanity pharmaceutically defenseless against the Covid-19 pandemic. Since CoVs have repeatedly challenged civilization for the past 20 years, and with the widespread dispersion of SARS-CoV-2 infections, we can expect CoVs to be a major contributor to future diseases along with influenza and antibiotic resistant bacteria. The capacitance for CoVs to genetically recombine and zoonotically jump also reveals a growing vulnerability in disease prevention strategies, especially in rural areas. Increasing globalization and rapid development into rural areas allows infectious diseases to spread into cities and other countries, leading more easily to pandemics [402].

Predicting the next epidemic disease is computationally impractical and requires massive surveillance. Nevertheless, hindering acquisition of infectious diseases can be achieved through widespread education and distribution of sanitary equipment. Such practices were performed in Africa to limit the spread of diarrheal diseases and attenuate the spread of Ebola [403,404]. In the meantime, research for antivirals and a vaccine against the SARS-CoV-2 may lead to solutions against the Covid-19 pandemic, and possibly future CoVs.

**Author Contributions:** Both authors contributed significantly to the conceptualization of this review, but N.A.W. initially conceived of the project. For the methodology, validation, formal analysis and data curation, both authors contributed equally, but N.A.W. designed the format and verified the primary conclusions. Both authors contributed to the writing of the original drafts and the editing. M.H.S.J. conducted the project administration and was responsible for funding acquisition. Both authors have read and agreed to the published version of the manuscript. Authorship is limited to those who have contributed substantially to the work reported. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the U.S. National Institutes of Health, gran<sup>t</sup> number GM077402.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Acknowledgments:** We would like to acknowledge the contribution of Zhongge Zhang and Luis Arturo Medrano-Soto for useful discussion, and the latter for the analyses necessary to generate Figures 3 and 4. We are thankful for the artistic representation of the Coronavirus replication cycle in Figure 2, illustrated by Yatavee Vajaphattana.

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