# Structurally Modified Bioactive Peptide Inhibits SARS-CoV-2 Lentiviral Particles Expression
## 1 Introduction  
The current coronavirus disease 2019 (COVID-19) outbreak since its beginning in Wuhan, China has become a global health emergency [1, 2]. The causative novel virus, a _Betacoronavirus_, was named the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or 2019-nCoV) owing to its high homology (\(\sim\)80%) to another respiratory virus SARS-CoV [3]. As of September 2022, around 614,215,882 cases worldwide have been reported according to the John Hopkins University (Available on: [[https://coronavirus.jhu.edu/map.html](https://coronavirus.jhu.edu/map.html)]([https://coronavirus.jhu.edu/map.html](https://coronavirus.jhu.edu/map.html)), accessed on 23 September 2022). Clinically, the SARS-CoV-2 virus predominantly affects the pulmonary system but some evidence for active SARS-CoV-2 infection outside of the respiratory tract is slowly emerging [4; 5; 6]. COVID-19 in many cases results in severe respiratory illness such as an acute respiratory distress syndrome (ARDS) and multi-organ dysfunction, whereas cough, dyspnoea, accompanied by fever are the key initial symptoms of the disease [7]. Recent literature reports also indicate neurological symptoms such as headache, varied mental status, memory loss, depression, and anosmia, in many patients with COVID-19 [8; 9]. However, in some cases, COVID-19 infection may even exhibit an asymptomatic state [10], while weaker pathogenesis has been observed in neonates, infants, and children as well [11; 12]. Further, long-lasting COVID-19 or \"long COVID\" is characterized by parallel symptoms of fatigue, headache, dyspnea, and anosmia over a period of 4-12 weeks or more [13]. Apart from system level physiological changes, SARS-CoV-2 infection also impairs oxidative phosphorylation (OXPHOS), leading to augmented oxidative stress [14]. In our recent article, we summarized key clinical features of SARS-CoV-2 [15] and further seminal readings are available for detailed study as well [13; 16; 17]. The current clinical management of COVID-19 is largely supportive with no specialized targeted therapy, thus, overwhelming healthcare systems [18]. However, the recent discovery and characterization Paxlovid along with monoclonal antibodies and remdesivir may revolutionize COVID-19 treatment [19; 20]. Further emergence of several variants of SARS-CoV-2, owing to intense pressure on the virus to genetically evolve in light of mRNA vaccination is another global challenge [21]. In a previous manuscript, we proposed developing peptide based pharmaceutics to inhibit specific SARS-CoV-2 pathophysiologic processes [15]. Some of the key pharmacological approaches included blocking the Angiotensin-Converting Enzyme 2 (ACE2), Transmembrane Serine Protease 2 (TMPRSS2), and furin processing by peptides substrates containing arginine, isoleucine, or leucine [15; 22]. The scientific rationale behind the selection of these targets was based on the utilization of ACE2, TMPRSS2, and furin cleavage by SARS-CoV-2 spike (S) protein for cellular entry and processing [23; 24]. Moreover, peptide substrates with arginine and hydrophobic isoleucine can bind to the large hydrophobic S1 pocket of TMPRSS2, possibly resulting in blockade of SARS-CoV-2 [25]. Likewise, arginine containing potent peptide based furin inhibitors have been developed [26; 27]. Besides, peptides have several advantages over proteins or antibodies owing to their small size, easy synthesis, and cellular delivery through the membranes of cells [28]. Considering the critical need of therapeutics for the COVID-19 pandemic, drug or nutraceutical repurposing has gained impetus in medical research to find candidates for this new indication. Based on the idea that SARS-CoV-2 spike protein and ACE2 on the host cell surface is of great importance to initiate COVID-19 infection, we designed multiple analogs of ACE2 modulating hydrophobic peptide IRW (Ile-Arg-Trp) with unique terminal moieties.