The Life Cycle of SARS-COV-2 and Potential Targets for Drug Development
The life cycle of the virus includes early-stage events and later-stage events (Figure 1a,b). In the first stage, the virus utilizes its spike (S) protein to bind to angiotensin converting enzyme 2 (ACE2) on the host cell membrane [13,14]. The virus enters the host cell after the spike S protein-ACE2 complex is proteolytically activated by transmembrane protease serine 2 (TMPRSS2) (see (b) in Figure 1), which eventually permits the virus-host cell fusion and the release of the viral RNA genome [15]. Alternatively, the bound virus spike S protein can also be proteolytically activated by furin [16]. Further processing is promoted by cathepsins in (endo)lysosomes to ultimately aid in the viral envelope fusion with the host membranes and the release of the viral genome (see (a) in Figure 1) [17].
The RNA genome of SARS-CoV-2 has more than 29,800 nucleotides which encode for about 29 proteins: nonstructural proteins (NSPs; 16 proteins), structural proteins (4 proteins), and accessory proteins (9 proteins) [18,19]. The structural proteins are spike S protein, envelope (E) and membrane (M) proteins which form the viral envelope, and nucleocapsid (N) protein which binds to the virus RNA genome. In the post-entry phase of the virus life cycle (Figure 1), the NSPs domain is expressed as two polypeptides which, after processing, produce papain like protease (PLpro) (NSP3), main protease (Mpro) (also known as 3-chymotrypsin-like protease (3CLpro); NSP5) [20], and RNA-dependent RNA polymerase (RdRp; NSP12) [21]. Initial processing of the two polypeptides is promoted by host proteases, and then, is propagated by the action of the viral PLpro and Mpro. The viral RdRp is also responsible for the replication and amplification of the viral genome. The viral RNA and the N structural protein are biosynthesized in the host cell cytoplasm, whereas other viral structural proteins including S, M, and E are eventually biosynthesized in the endoplasmic reticulum and transported to the Golgi apparatus. The viral RNA–N complex and S, M, and E proteins are then assembled in the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) to produce a mature virus particle. The mature virus is then released from the Golgi apparatus via a budding process and next from the host cells by exocytosis (Figure 1) [12,22,23,24].
Collectively, the goal of antiviral therapeutics is to inhibit one or more events in the life cycle of the virus in order to impede the propagation of infection. Along these lines, any protein or event in the virus life cycle can be considered as a molecular target for anti-COVID-19 drug development efforts. In this review, we describe the antiviral agents that are currently being tested in clinical trials to block and/or inhibit the advanced events of the virus life cycle. Although the majority of the presented antiviral therapeutics target the viral polymerase or the viral proteases, few other therapeutics target other molecular targets (Table 1).