Therapeutic Effectiveness and Safety of Repurposing Drugs for the Treatment of COVID-19: Position Standing in 2021

Abstract

COVID-19, transmitted by SARS-CoV-2, is one of the most serious pandemic situations in the history of mankind, and has already infected a huge population across the globe. This horrendously contagious viral outbreak was first identified in China and within a very short time it affected the world's health, transport, economic, and academic sectors. Despite the recent approval of a few anti-COVID-19 vaccines, their unavailability and insufficiency along with the lack of other potential therapeutic options are continuing to worsen the situation, with valuable lives continuing to be lost. In this situation, researchers across the globe are focusing on repurposing prospective drugs and prophylaxis such as favipiravir, remdesivir, chloroquine, hydroxychloroquine, ivermectin, lopinavir-ritonavir, azithromycin, doxycycline, ACEIs/ARBs, rivaroxaban, and protease inhibitors, which were preliminarily based on in vitro and in vivo pharmacological and toxicological study reports followed by clinical applications. Based on available preliminary data derived from limited clinical trials, the US National Institute of Health (NIH) and USFDA also recommended a few drugs to be repurposed i.e., hydroxychloroquine, remdesivir, and favipiravir. However, World Health Organization later recommended against the use of chloroquine, hydroxychloroquine, remdesivir, and lopinavir/ritonavir in the treatment of COVID-19 infections. Combining basic knowledge of viral pathogenesis and pharmacodynamics of drug molecules as well as in silico approaches, many drug candidates have been investigated in clinical trials, some of which have been proven to be partially effective against COVID-19, and many of the other drugs are currently under extensive screening. The repurposing of prospective drug candidates from different stages of evaluation can be a handy wellspring in COVID-19 management and treatment along with approved anti-COVID-19 vaccines. This review article combined the information from completed clinical trials, case series, cohort studies, meta-analyses, and retrospective studies to focus on the current status of repurposing drugs in 2021.

Keywords: COVID-19; doxycycline; favipiravir; hydroxychloroquine; ivermectin; remdesivir; repurposing drugs; rivaroxaban.

FIGURE 1

Remdesivir, an investigational nucleotide analogue, and its triphosphate possessing resemblance with Adenosine triphosphate can compete with it to act as a substrate for various viral RNA polymerase inhibiting RNA synthesis. Remdesivir triphosphate form adds to the growing RNA chain more efficiently than ATP, causing chain termination at 3 nucleotides downstream, and displays anti-COVID-19 efficacy.

FIGURE 2

Different modes of Anti-COVID-19 actions of Doxycycline including inhibition of viral replication and positive sense single-stranded RNA replication along with chelation with Zn on MMPs and downregulation of inflammatory cytokines.

FIGURE 3

Azithromycin exerts inhibition of uncoating of coronaviruses, amplification of host’s interferon (IFN) pathway-mediated antiviral responses resulting in a reduction of viral replication, interference in the binding interaction of SARS-CoV-2 spike protein and host receptor ACE2 protein as well as viral endocytosis.

FIGURE 4

ACE2 downregulation by ACEIs/ARBs. Inhibition of RNA-dependent RNA Polymerase and main protease by, respectively, Favipiravir and Lopinavir/Ritonavir. Cessation of viral fusion onto the cell membrane and endocytosis by increasing the cell pH by Hydroxychloroquine/Chloroquine. Inhibition of transmembrane protease serine 2 (TMPRSS2) by rivaroxaban which can potentially block the viral entry of SARS-CoV-2 into the host by ceasing the fragmentation of spike protein into the S1 and S2 subunits.

FIGURE 5

Ivermectin demonstrates anti-COVID-19 action by inhibiting nuclear transport resulted by destabilization of IMP-α/β complex which ultimately damages RNA viruses.