Potential Therapeutic Agents
Potent therapeutics to combat SARS-CoV-2 infection include virus binding molecules, molecules or inhibitors targeting particular enzymes implicated in replication and transcription process of the virus, helicase inhibitors, vital viral proteases and proteins, protease inhibitors of host cells, endocytosis inhibitors, short interfering RNA (siRNA), neutralizing antibodies, MAbs against the host receptor, MAbs interfering with the S1 RBD, antiviral peptide aimed at S2, and natural drugs/medicines (7, 166, 186). The S protein acts as the critical target for developing CoV antivirals, like inhibitors of S protein and S cleavage, neutralizing antibodies, RBD-ACE2 blockers, siRNAs, blockers of the fusion core, and proteases (168).
All of these therapeutic approaches have revealed both in vitro and in vivo anti-CoV potential. Although in vitro research carried out with these therapeutics showed efficacy, most need appropriate support from randomized animal or human trials. Therefore, they might be of limited applicability and require trials against SARS-CoV-2 to gain practical usefulness. The binding of SARS-CoV-2 with ACE2 leads to the exacerbation of pneumonia as a consequence of the imbalance in the renin-angiotensin system (RAS). The virus-induced pulmonary inflammatory responses may be reduced by the administration of ACE inhibitors (ACEI) and angiotensin type-1 receptor (AT1R) (207).
Several investigations have suggested the use of small-molecule inhibitors for the potential control of SARS-CoV infections. Drugs of the FDA-approved compound library were screened to identify four small-molecule inhibitors of MERS-CoV (chlorpromazine, chloroquine, loperamide, and lopinavir) that inhibited viral replication. These compounds also hinder SARS-CoV and human CoVs (208). Therapeutic strategies involving the use of specific antibodies or compounds that neutralize cytokines and their receptors will help to restrain the host inflammatory responses. Such drugs acting specifically in the respiratory tract will help to reduce virus-triggered immune pathologies in COVID-19 (209). The later stages of coronavirus-induced inflammatory cascades are characterized by the release of proinflammatory interleukin-1 (IL-1) family members, such as IL-1 and IL-33. Hence, there exists a possibility that the inflammation associated with coronavirus can be inhibited by utilizing anti-inflammatory cytokines that belong to the IL-1 family (92). It has also been suggested that the actin protein is the host factor that is involved in cell entry and pathogenesis of SARS-CoV-2. Hence, those drugs that modulate the biological activity of this protein, like ibuprofen, might have some therapeutic application in managing the disease (174). The plasma angiotensin 2 level was found to be markedly elevated in COVID-19 infection and was correlated with viral load and lung injury. Hence, drugs that block angiotensin receptors may have potential for treating COVID-19 infection (121). A scientist from Germany, named Rolf Hilgenfeld, has been working on the identification of drugs for the treatment of coronaviral infection since the time of the first SARS outbreak (19).
The SARS-CoV S2 subunit has a significant function in mediating virus fusion that provides entry into the host cell. Heptad repeat 1 (HR1) and heptad repeat 2 (HR2) can interact and form a six-helix bundle that brings the viral and cellular membranes in close proximity, facilitating its fusion. The sequence alignment study conducted between COVID-19 and SARS-CoV identified that the S2 subunits are highly conserved in these CoVs. The HR1 and HR2 domains showed 92.6% and 100% overall identity, respectively (210). From these findings, we can confirm the significance of COVID-19 HR1 and HR2 and their vital role in host cell entry. Hence, fusion inhibitors target the HR1 domain of S protein, thereby preventing viral fusion and entry into the host cell. This is another potential therapeutic strategy that can be used in the management of COVID-19. Other than the specific therapy directed against COVID-19, general treatments play a vital role in the enhancement of host immune responses against the viral agent. Inadequate nutrition is linked to the weakening of the host immune response, making the individual more susceptible. The role played by nutrition in disease susceptibility should be measured by evaluating the nutritional status of patients with COVID-19 (205).