**2. SARS-CoV-2 life cycle and potential targets**

The rationale major biochemical events and components in the replication cycle of coronavirus are considered as targets for currently developed drugs. These include the spike protein, proteolytic enzymes, and RNA-dependent RNA polymerase [24]. SARS-CoV-2 is transmitted mainly via respiratory droplets. The virus enters the host cells through two pathways, either via endosomes or plasma membrane fusion. In both mechanisms, the viral S protein mediates attachment to the membrane of the host cell and engages ACE2 as the entry receptor [25]. A host protease termed transmembrane serine protease 2 (TMPRSS2) activates the connection between S protein and ACE-2 [26]. S protein is used by the virus to destroy antibodies and make it simpler for it to attach to host receptors [27]. Beta-coronaviruses generally employ hemagglutinin-esterase (HE) to bind to sialic acid on the glycoprotein surface, despite the fact that the fusion machinery of SARS-CoV-2 remains unknown [28]. Fusion inhibitors might be used to prevent these fusion stages.

The envelope is peeled off when fusion is complete, and the SARS-CoV-2 genome, together with its nucleocapsid, penetrates the cytoplasm of the host cell. Its genome comprises the open reading frames 1a and 1b (ORF1a and ORF1b) genes, which create two polyproteins (pp) named pp1a and pp1b, which aid in the viral translation process by hijacking host ribosomes [29]. Main protease (Mpro) and papain-like protease (Ppro) break these polyproteins to create multiple non-structural proteins [30]. Aside from Mpro and Ppro, SARS-CoV-2 has 3C-like cysteine protease (3CLPro), which has a 96% resemblance to SARS-CoV. These proteases are essential for viral replication and transcription, and protease inhibitors inhibiting these proteases are potential antivirals for SARS-CoV-2. The promising clinical outcomes for COVID-19 patients should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs [31–34]. Moreover, clinical trials with these drugs should be performed on COVID-19 patients to prove their efficacy and safety as proposed for tocilizumab (**Figure 1**) [35].

#### **Figure 1.** *Schematic diagram of the life cycle of SARS-CoV-2.*
