A comprehensive review on pharmacologic agents, immunotherapies and supportive therapeutics for COVID-19

Abstract

The emergence of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected many countries throughout the world. As urgency is a necessity, most efforts have focused on identifying small molecule drugs that can be repurposed for use as anti-SARS-CoV-2 agents. Although several drug candidates have been identified using in silico method and in vitro studies, most of these drugs require the support of in vivo data before they can be considered for clinical trials. Several drugs are considered promising therapeutic agents for COVID-19. In addition to the direct-acting antiviral drugs, supportive therapies including traditional Chinese medicine, immunotherapies, immunomodulators, and nutritional therapy could contribute a major role in treating COVID-19 patients. Some of these drugs have already been included in the treatment guidelines, recommendations, and standard operating procedures. In this article, we comprehensively review the approved and potential therapeutic drugs, immune cells-based therapies, immunomodulatory agents/drugs, herbs and plant metabolites, nutritional and dietary for COVID-19.

Keywords: Drug; immunotherapeutic; nutrition; supportive therapy; viral inhibitor.

Figure 1.

Viral entry inhibitors. The virus enters target cells through binding to human angiotensin-converting enzyme 2 (ACE2) receptor. The antiviral drugs target this viral binding and viral entry preventing the virus entering the cells and therefore block viral replication inside the host cells. Some potential drugs are given in the red. These drugs work through inhibiting interaction of SAR-CoV-2 protein with the ACE2 receptor or disrupting endocytosis.

Figure 2.

Viral replication inhibitors. Following entry of the virus into the host cell, the viral RNA is translated and replicated to produce viral genome and viral protein. Viral genome and viral proteins are assembled in the cytoplasm to form virion progeny. Virions are then released from the infected cell through exocytosis. The viral replication inhibitors block viral replication inside the host cells and thereby reducing viral multiplication. These drugs include protease inhibitors, RNA-dependent RNA polymerase inhibitors, and RNA replication inhibitors and the names of the potential drugs within each group are given in red.

Figure 3.

Host immune response modulators. In the early stage of infection, SARS-CoV-2 virus enters alveoli and infects type II pneumocytes. In response to the viral infection, the pneumocytes produce type I interferon (IFN). Macrophages also identify the virus and produce cytokines such as Interleukin 1 (IL-1), IL-6, IL-8, IL-12 and tumor necrosis factors (TNF). Macrophages as antigen presenting cells activate the helper and cytotoxic T cells. The activated T cells produce cytokines and attack infected cells. In this period, therapeutic strategies to boost immune response can be applied, for example IFN-α-2b treatment. At the later stage, the pro-inflammatory cytokines recruit more immune cells, such as monocytes and neutrophils, which in turn produce more cytokines that result in a condition known as “cytokine storm”. The severe inflammation damages the lung leading to fibrin deposition and fluid leakage. In this period, therapeutic strategies to reduce the inflammatory response are applicable.

Figure 4.

The genomic organization of SARS-CoV-2 along with the major drug targets that can be utilized for developing SARS-CoV-2 specific therapeutics.

Figure 5

· Chemical structure of some major therapeutic drugs that have been evaluated against SARS-CoV-2: chloroquine, hydroxychloroquine, oseltamivir, lopinavir, remdesivir, titonavir, favipiravir, tibavitin, umifenovir, danoprevir, camostat, nafamostat, baricitinib, nitazoxanide, ivermectin, fedratinib, and dexamethasone.

Figure 6.

The major natural constituents present in herbal plants that can target and inhibit pathways and proteins of SARS-CoV-2 such as spike protein, RdRp, 3CL^pro, PL^pro, and helicase. inhibit pathways and proteins of SARS-CoV-2 such as spike protein, RdRp, 3CL^pro, PL^pro, and helicase.