Potential Treatments
At present, no drugs have been approved for the treatment of COVID-19. Most drugs are targeted at different phases in the SARS-CoV-2 life cycle and a few drugs mediate the hyperinflammation associated with the viral infection. There are 5 main categories of anti-COVID drugs.
1. Spike protein
SARS-CoV-2 engages cellular protease TMPRSS2 and furin for S protein priming for viral entry into target cells. Furin protease pre-cleavages S protein at the S1/S2 site, which facilitates subsequent TMPRSS2-dependent entry into host cells. Blocking these pathways can reduce viral entry. Proprotein convertase inhibitor α1-PDX is shown to be able to inhibit cleavage activity [23]. Serine protease inhibitor camostat mesylate, which blocks TMPRSS2 activity, has been demonstrated a significant reduction in SARS-2-S-driven entry into the lungs [7].
2. SARS-CoV-2 receptor ACE2
Soluble ACE2 or an Fc domain fused to ACE2 that may act as a decoy to direct SARS-CoV-2 away from endogenous ACE2 and itself bind the invading virus [4]. The soluble ACE2 circulates in the bloodstream and acts as a competitive interceptor of SARS-CoV-2 from binding to the full-length ACE2 anchored in the cell membrane. This prevents the virus from cell entry, multiplication, and further cell damage.
Another strategy under clinical trials is that an antibody or a single-chain antibody fragment (scFv) that binds ACE2 and therefore blocks the interaction of spike protein to ACE2 [4].
3. Interfering with proteolysis mechanism of the virus within host cells
After entering the host cell, the viral single-stranded positive RNA is released and translated into two polyproteins, pp1a and pp1ab, which encode for two proteinases, 3-chymotrypsin-like proteinase (3CLpro) and papain-like proteinase (PLpro). 3CLpro and PLpro cleave the polyproteins translated from viral RNA into functional proteins for viral replication ad assembly [31]. Therefore, inhibiting the activity of this enzyme would block viral replication. Drugs that target these two proteases in other viruses, such as lopinavir and ritonavir, have been tested in patients with mild and moderate infection with COVID-19. However, no benefit was observed with the treatment. The efficacy of combination therapy of lopinavir/ritonavir and IFN-β1b is being studied in a clinical trial [4].
4. Interfering with replication, transcription, and translation of virus
RNA-dependent RNA polymerase plays a major role in assisting in viral translation and replication. Many existing nucleotide drugs such as remdesivir, favipiravir, ribavirin, galidesivir, and EIDD-2801 target RNA-dependent RNA polymerase. All of the drugs have the ability to inhibit RNA-dependent RNA polymerase. The National Institutes of Health’s clinical trial showed that remdesivir shortened the recovery time, as remdesivir outperformed placebo by demonstrating a 31% faster time to recovery [4].
5. Anti-inflammatory and immunomodulators in the control of cytokine storm
The immune system is hyper-stimulated by the virus, resulting in a cytokine storm with an increase in inflammatory cytokines such as IL-2, IL-6, IL-7, and tumor necrosis factor-α (TNF-α). The cytokine storm also leads to secondary hemophagocytic lymphohistiocytosis (sHLH) and tissue damage. A large number of approved anti-inflammatory and/or immunomodulatory drugs used for other diseases targeting cytokines are studied for the potential treatment of COVID-19 [4].
Chloroquine (CQ) and hydroxychloroquine (HCQ) are approved for the treatment of malaria and have antiviral activity against hepatitis B, HIV, H1N1, and Zika virus [30]. CQ and HCQ interfere with terminal glycosylation of ACE2, increase the pH of endosomes, therefore reducing viral release into host cells. By altering membrane stability, signaling pathways, and transcriptional activity, CQ and HCQ inhibit cytokine production and modulation of costimulatory molecules. Studies have shown that CQ and HCQ inhibit antigen presentation in dendritic cells and cytokine production by leukocytes, Toll-like receptors, and immune cells [31].
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