1. Introduction
Over the last 20 years, humanity has dealt with three serious coronavirus infection outbreaks, namely severe acute respiratory syndrome coronavirus (SARS-CoV, 2002–2003) [1], Middle East respiratory syndrome coronavirus (MERS-CoV, 2012–2019) [2], and SARS-CoV-2, (2019-present) [3]. Although it appears that the fatality rates for the first two outbreaks are much higher (9.2% and 37%, respectively) than the ongoing pandemic (~3.3% as of 5 September 2020) [4,5], the ongoing infectious disease of SARS-CoV-2 appears to be far more contagious. The ongoing outbreak, widely known as coronavirus disease of 2019 (COVID-19), was recognized by the World Health Organization as a global pandemic on 11 March 2020 [6]. As of 5 September 2020, there have been more than 26.7 million confirmed cases worldwide with more than 876 thousand global deaths [4].
Efforts are ongoing to deliver an effective vaccine to protect individuals against the disease. Likewise, potential therapeutics to prevent and/or treat the disease and its complications are being advanced to clinical trials all around the world. In this direction, effective treatments for COVID-19 patients, particularly those who have the severe version of the disease and become critically ill needing hospitalization, intensive care unit (ICU) admission, and mechanical ventilation, appear to include antiviral drugs as well as anti-inflammatory drugs and anticoagulant drugs to also treat the associated cytokine storm [7] and coagulopathies [8], respectively.
Considering the current clinical guidelines, remdesivir has been recommended for the treatment of COVID-19 in hospitalized patients with severe disease [9]. Furthermore, favipiravir has been approved for the treatment of COVID-19 in the hospital settings in few countries [10]. Moreover, dexamethasone as an anti-inflammatory drug has also been recommended in patients with COVID-19 who require mechanical ventilation or supplemental oxygen [11]. Despite the above recommendations and/or approvals, the need for effective treatment remains largely unmet. Therefore, a large number of potential therapeutics continue to be developed and others are being advanced into clinical trials. We recently reviewed the chemical and mechanistic aspects of antiviral drugs that block the early phase of the virus life cycle [12]. In this article, we review the chemical structures and the mechanisms of action of potential antiviral therapeutics that block/inhibit the post-entry stages of the virus life cycle. We only include those therapeutics that are listed in clinicatrials.gov. They include both old drugs and new molecular entities. Many of the potential therapeutics are small molecules and few are macromolecules. Some of these therapeutics also possess anti-inflammatory effects.

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).