The Rationale for Potential Pharmacotherapy of COVID-19

Abstract

On 11 March 2020, the coronavirus disease (COVID-19) was defined by the World Health Organization as a pandemic. Severe acute respiratory syndrome-2 (SARS-CoV-2) is the newly evolving human coronavirus infection that causes COVID-19, and it first appeared in Wuhan, China in December 2019 and spread rapidly all over the world. COVID-19 is being increasingly investigated through virology, epidemiology, and clinical management strategies. There is currently no established consensus on the standard of care in the pharmacological treatment of COVID-19 patients. However, certain medications suggested for other diseases have been shown to be potentially effective for treating this infection, though there has yet to be clear evidence. Therapies include new agents that are currently tested in several clinical trials, in addition to other medications that have been repurposed as antiviral and immune-modulating therapies. Previous high-morbidity human coronavirus epidemics such as the 2003 SARS-CoV and the 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) prompted the identification of compounds that could theoretically be active against the emerging coronavirus SARS-CoV-2. Moreover, advances in molecular biology techniques and computational analysis have allowed for the better recognition of the virus structure and the quicker screening of chemical libraries to suggest potential therapies. This review aims to summarize rationalized pharmacotherapy considerations in COVID-19 patients in order to serve as a tool for health care professionals at the forefront of clinical care during this pandemic. All the reviewed therapies require either additional drug development or randomized large-scale clinical trials to be justified for clinical use.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; baricitinib; chloroquine; favipiravir; interferons; lopinavir; remdesivir.

Figure 1

Virus entry into the host cell. The attachment protein “-spike glycoprotein” of the severe acute respiratory syndrome-2 (SARS-CoV-2) uses a cellular attachment factor (angiotensin-converting enzyme 2 (ACE2)) and uses the cellular protease TMPRSS2 (transmembrane protease serine 2) for its activation. ACE2 can be activated via either losartan or recombinant human ACE 2 (rhACE2). Potential pharmacotherapeutic approaches include the use of camostat mesylate (which is a TMPRSS2 inhibitor) to block the priming of the spike protein, increasing the number of ACE2 receptors via losartan, and the use of soluble recombinant human ACE2 (which should slow viral entry into cells via competitive binding with SARS-CoV-2). The structure of SARS-CoV-2 is shown in the upper right.

Figure 2

Inflammatory responses triggered by SARS-CoV-2 infection. Two inflammatory pathways may be distinguished. The primary pathway occurs as an early response to viral infection before the development of neutralizing antibodies (NAb). The secondary pathway begins with the release of Nab, which signifies the development of adaptive immunity. Triggering the FcR-mediated-inflammatory response is mediated by the virus-NAb complex and may lead to acute lung injury through several pathways including the release of monocyte chemoattractant protein-1 and interleukin-8 (IL-8) from macrophages.