In March 2020, the COVID-19 disaster befell the entire humanity claiming ever since millions of lives the world over. The physical and mental trauma notwithstanding, mankind has fought back – thanks to the venerable commitment and dedication of scientific researchers in different countries and the commendable initiatives of some leading pharmaceutical biotech companies, multiple therapeutics to combat the apparently indomitable disease have arrived in the market.
Since October 2020, the United States Food and Drug Administration (US FDA) has approved the use of a few drugs for the treatment of COVID-19. These drugs target the molecules responsible for either the viral replication or virus-triggered pathogenesis.
Target: RNA-dependent RNA polymerase (RdRp)
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus contains a single stranded positive-sense RNA genome. After entering the susceptible cell, the genome functions as a messenger RNA (mRNA) which is translated leading to the synthesis of sixteen non-structural proteins (NSP 1-16). Of these, the catalytic NSP12, together with the accessory proteins NSP7 and NSP8, constitutes an RNA dependent RNA polymerase (RdRp) – the replication/transcription machinery of the virus.
Remdesivir is a prodrug that mimics the structure of adenosine. As it enters the cell, it is metabolized (phosphorylated) to an active nucleotide triphosphate (NTP) analog called remdesivir triphosphate (RTP). The RdRp can use RTP as a substrate to incorporate remdesivir monophosphate (RMP) into the growing RNA strand. RMP mimics adenosine monophosphate (AMP) and forms Watson-Crick base pair with uridine monophosphate (UMP). Incorporation of remdesivir into the growing RNA product allows the addition of three more nucleotides downstream before terminating RNA synthesis – remdesivir is a “chain terminator”. Developed by Gilead Sciences, Inc., one of the leading biotech companies of the United States, remdesivir is sold under the brand name of Veklury. In October, 2020, it obtained FDA approval
Calming the “storm”
COVID-19 results in immunopathological phenomena triggered by what is known as the “cytokine storm”. Normally, cytokines are part of the body’s immune response to infection. However, immune dysregulation causes an excessive production of cytokines with toxic effect.
Cytokines act via specific cytokine receptors. The human genome codes for over 40 cytokine receptors, all of which signal via Janus (protein) kinases such as JAK1 and JAK2. Inhibitors to these kinases have emerged as useful therapeutic tools for COVID-19 infection.
In May 2022, the FDA approved the use of Baricitinib for the treatment of COVID-19. Baricitinib is a JAK inhibitor – it enters the ATP-binding pocket of the active conformation of JAK2. By inhibiting the actions of JAK1 and JAK2, it mitigates JAK-mediated inflammation and immune response, thus “calming the cytokine storm”.
Immunotherapy
An alternative approach to dampen the cytokine storm in COVID-19 infection has been immunotherapy targeting interlukin-6 receptor (IL-6R). Interlukin-6 (IL-6) is produced in response to infections and tissue injuries and contributes to host defense by stimulating acute phase responses, hematopoiesis and immune reactions. The expression of IL-6 is strictly controlled by transcriptional and posttranscriptional mechanisms – dysregulation results in pathological effects.
Tocilizumab is a humanized monoclonal antibody that targets IL-6R which exists in both soluble and membrane-bound forms. Consequently, it blocks the binding and signaling of IL-6. Tocilizumab has been granted the FDA approval for COVID-19 treatment in December 2022.
Blocking the protease
CoV-2 main protease, Mpro (also referred to as 3CL-protease), is a cysteine protease that is crucial for the processing of two virus-encoded polyproteins, pp1a and pp1ab. The protease cleaves these polyproteins into shorter, nonstructural proteins essential for replication of CoV-2. Hence, small molecule inhibitors of Mpro have been considered as useful therapeutics for the treatment of COVID-2.
Nirmatrelvir enters a binding pocket in Mpro and blocks its protease activity. It is packaged with ritonavir as Paxlovid. Co-administration with a low dose of ritonavir helps slow the metabolism, or breakdown, of nirmatrelvir so that the drug remains active in the body for longer period of time. Paxlovid has recently been approved by the FDA for COVID-2 treatment.
Despite the impressive advances for the general population, challenges persist particularly for the inclusion of high-risk populations in clinical trials. Evidently, more studies are needed to further assess the impact of novel and repurposed COVID-19 drugs.