# Selective Control by _Pistacia vera_ L. and Its Carotenoid Zaxanthin on SARS-CoV-2 Virus
## 1 Introduction  
The continuous emergence of respiratory viruses with pandemic potential underscores the critical need for alternative antiviral treatments. Over the past 20 years, zoonotic transmission has led to the emergence of highly pathogenic strains of coronaviruses (CoV) in human populations, including SARS-CoV, MERS-CoV and, recently SARS-COV-2, the etiological agent of COVID-19. According to the International Commission on Taxonomy of Viruses (ICTV, 2021), SARS-CoV-2 is classified within the subgenus Sarbecoronavirus, genus Betacoronavirus, sub-family Orthocoronavirinae, family Coronavirus, phylum Pisuvriciota, kingdom Orthornavirae, domain Riboviria. Coronaviruses, particularly alpha and beta coronaviruses, typically infect mammalian species and cause mild seasonal infections affecting the upper respiratory system [1, 2]. SARS-CoV-2, like other human coronaviruses, contains four structural proteins (S, E, M, N) and sixteen non-structural proteins (NSP1-16), essential for RNA replication, transcription, and immune evasion [2; 3; 4]. The spike (S) protein, composed of S1 and S2 subunits, is crucial for the virus's ability to enter host cells. The S1 subunit binds to the cellular receptor angiotensin-converting enzyme 2 (ACE2), while the S2 subunit facilitates membrane fusion [5; 6; 7; 8]. This dual function of the spike protein underscores its importance in the viral life cycle and identifies it as a significant therapeutic target. By inhibiting the interaction between the S1 subunit and ACE2 or blocking the fusion process mediated by the S2 subunit, potential treatments can effectively prevent the virus from infecting host cells, thereby halting the progression of the infection. ACE2, identified as a functional host receptor for SARS-CoV-2, is abundant in various cell types, particularly in type 2 alveolar cells and the nasal epithelium [9; 10]. The altered expression of ACE2 is associated with the severity of COVID-19, especially in individuals with cardiovascular diseases and metabolic syndrome [11]. SARS-CoV-2 entry into host cells is facilitated by the cleavage of the spike protein, either by TMPRSS2 (Transmembrane Serine Protease 2) on the cell membrane or by cathepsin L within endosomes [8]. Variants of concern (VOC) have emerged, characterized by mutations that affect transmissibility, pathogenicity, and immune escape. For example, the Alpha variant (B.1.1.7) has mutations that stabilize the spike-ACE2 complex, increasing infectivity and mortality [12]. The Omicron variant, with over 30 mutations in the spike protein, shows significant immune escape and higher transmissibility [13; 14; 15] and prefers a TMPRSS2-independent mechanism to enter host cells [16] efficiently. Considering the emergence of SARS-CoV-2 variants and the virus's persistence, which challenge the current vaccines' effectiveness, the search for additional antiviral agents remains critical. However, traditional drug development approaches can take decades and cost billions of dollars, which significantly complicates the process of identifying new antivirals against current and emerging mutated strains [14]. In this context, natural products and dietary compounds have gained attention for their potential antiviral properties, offering a complementary approach to traditional pharmaceuticals [17; 18]. Pistachio extracts and zeaxanthin, a carotenoid found in various fruits and vegetables, have been previously noted for their antiviral, antioxidant, anti-inflammatory, and immunomodulatory potential [19]. These properties could play a role in inhibiting viral replication and enhancing immune responses. However, their inhibitory effect against SARS-CoV-2 has not been thoroughly investigated. The present study aimed to explore the antiviral potential of pistachio extracts and its carotenoid zeaxanthin against SARS-CoV-2, unveiling the mechanism responsible for the observed effect.