BACKGROUND
The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in over 680 million confirmed cases and 6.7 million deaths as of January 2023. The virus enters human cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in the heart, kidneys, gastrointestinal tract, lungs, and other tissues. While initial research focused on viral load and replication, severe disease is increasingly attributed to exaggerated host cell responses, including a cytokine storm. This review integrates current knowledge on coronavirus classification, structure, viral entry, host cell responses across multiple organ systems, and potential therapeutic agents, emphasizing drug repurposing strategies.
METHODS
This is a narrative review that synthesizes publicly available literature on SARS-CoV-2 biology, host–pathogen interactions, and clinical trials of repurposed drugs. The authors discuss the structural and nonstructural proteins of coronaviruses, the role of the ACE2 receptor and associated proteases, and the responses of immune cells, endothelial cells, respiratory epithelial cells, kidney cells, liver cells, and neural cells to infection. They also review a wide range of therapeutics, including antimalarials (chloroquine, hydroxychloroquine), antivirals (remdesivir, ribavirin, favipiravir, molnupiravir, galidesivir, and others), interferons, lopinavir/ritonavir, umifenovir, monoclonal antibodies (bamlanivimab, etesevimab, tocilizumab), antibiotics (azithromycin, teicoplanin), ACE inhibitors, and anti-inflammatory agents (corticosteroids, anakinra). The review also touches on clathrin-mediated endocytosis and computer-aided drug design.
KEY RESULTS
SARS-CoV-2 variants differ in replication efficiency and interferon response; Omicron variants show weaker replication and slower interferon response compared to early strains. ACE2 is expressed in type 2 alveolar cells, ciliated cells, goblet cells, endothelial cells, podocytes, tubular epithelial cells, enterocytes, cholangiocytes, hepatocytes, and neural cells. Severe COVID-19 is associated with increased serum levels of IL-6, IL-7, TNF, CCL2, CCL3, and an elevated neutrophil:lymphocyte ratio. T-cell lymphopenia is common, and patients who died showed increased expression of the death receptor FAS. In the lungs, SARS-CoV-2 replication is similar to that of SARS-CoV and influenza A/H1N1pdm09. Diarrhea occurs in up to 73% of patients within the first week. Liver enzyme elevations (AST, ALT, bilirubin) were observed in 21%, 22%, and 10% of patients, respectively. Among drug candidates, remdesivir was FDA-approved for hospitalized COVID-19 patients based on three randomized controlled trials; chloroquine and hydroxychloroquine were revoked due to lack of efficacy and cardiac adverse events. Dexamethasone reduced mortality by 20% in patients requiring oxygen or mechanical ventilation. Molnupiravir (EIDD-2801) was approved for emergency use in the UK and US, showing efficacy in reducing viral RNA in nasopharyngeal swabs. Tocilizumab decreased hospitalization duration, mechanical ventilation risk, and death in severe cases. However, many drugs (e.g., ribavirin, lopinavir/ritonavir, azithromycin, anakinra) showed no significant benefit or were associated with adverse events.
CLINICAL IMPLICATIONS
The review underscores that severe COVID-19 is driven by hyperinflammation and coagulation disturbances, not solely by viral load. ACE2 expression in multiple organs explains the wide clinical spectrum, including respiratory failure, acute kidney injury, liver dysfunction, and neurological symptoms. The success of remdesivir and molnupiravir highlights the importance of targeting the viral RNA-dependent RNA polymerase. Corticosteroids like dexamethasone are effective in the hyperinflammatory stage, but their use should be limited to severe cases. Monoclonal antibodies targeting the spike protein have been hampered by variant emergence. The review calls for continued research into host-directed therapies, such as ACE2 inhibitors and immunomodulators, and emphasizes the need for robust clinical trials to evaluate safety and efficacy, particularly in the context of emerging variants. The lessons from drug failures (e.g., hydroxychloroquine, lopinavir/ritonavir) should inform future therapeutic design.