# Selective Control by _Pistacia vera_ L. and Its Carotenoid Zaxanthin on SARS-CoV-2 Virus
## 5 Conclusions  
Our results indicated that pistachio extracts and zeaxanthin possessed a selective inhibitory effect on the entry of specific SARS-CoV-2 variants, with a notable reduction in the ability of the omicron variant to enter host cells. Interestingly, zeaxanthin did not exhibit the same inhibitory effect on the alpha variant's entry. However, zeaxanthin appears to modulate host cell factors, mainly by reducing the expression of TMPRSS2, a protease involved in the entry of the alpha variant. This suggests that while zeaxanthin may not directly hinder the alpha variant's binding, it still offers protective effects by reducing the availability of this crucial host factor for viral entry.  
Molecular modeling and MD simulations revealed zeaxanthin's stronger interaction with the o-RBD than the alpha variant, showing greater stability and favorable binding affinity (\(-8.77\) kcal/mol). This correlates with reduced viral entry in vitro, suggesting zeaxanthin destabilizes RBD-ACE2 binding.  
Furthermore, the observation that zeaxanthin is a potent inhibitor of viral proteases strengthens its potential as a broad-spectrum antiviral agent. By targeting both viral entry mechanisms and protease activity, zeaxanthin provides a multifaceted approach to preventing viral infection. These findings highlight its potential for emerging specific variants and as a general therapeutic agent against SARS-CoV-2, capable of offering protection across different variants. The dual inhibitory action of zeaxanthin on both the virus and host factors associated with viral entry underscores its promise as an effective treatment strategy for managing COVID-19, particularly in the face of evolving variants.  
Lastly, zeaxanthin's ability to inhibit viral entry and reduce the expression of critical host factors, combined with its effectiveness against viral proteases, positions it as a valuable broad-spectrum inhibitor. Future studies should explore its potential in clinical settings, particularly in combination therapies, to fully assess its efficacy in managing infections caused by various SARS-CoV-2 variants.  
The following supporting information can be downloaded at [[https://www.mdpi.com/article/10.3390/ijms26041667/s1](https://www.mdpi.com/article/10.3390/ijms26041667/s1)]([https://www.mdpi.com/article/10.3390/ijms26041667/s1](https://www.mdpi.com/article/10.3390/ijms26041667/s1)).  
Conceptualization, M.T.S., G.M. and R.P.; methodology, R.P., P.T. and D.G.; software, R.P. and A.R.; investigation, R.P., D.G., D.B. and P.T.; data curation, R.P., M.T.S. and G.M.; writing--original draft preparation, R.P., D.G., P.T., D.B. and G.M.; writing--review and editing, R.P., D.G., A.R. and M.T.S.; visualization, R.P., D.G. and P.T.; supervision, M.T.S., G.M., A.R. and R.P.; project administration, M.T.S. and G.M.; funding acquisition, M.T.S. and G.M. All authors have read and agreed to the published version of the manuscript.  
This work was funded by American Pistachio Growers (APG), Fresno, CA (USA).  
Not applicable.  
The data presented in this study are available on request from the corresponding author.  
We thank [PERSON] (Universite Paris-Saclay, INRAE, UVSQ, Virologie et Immunologie Moleculaires, Jouy-en-Josas, France) for providing plasmids for pseudovirus construction and [PERSON] (University of Torino, Italy) for providing A549 cells. We thank the American Pistachio Growers (APG) for providing the pistachios used in this study.  
The authors declare no conflicts of interest.