Targeting cyclooxygenase enzyme for the adjuvant COVID‐19 therapy

Abstract

Despite vigorous efforts, the COVID‐19 pandemic continues to take a toll on the global health. The contemporary therapeutic regime focused on the viral spike proteins, viral 3CL protease enzyme, immunomodulation, inhibition of viral replication, and providing a symptomatic relief encouraged the repurposing of drugs to meet the urgency of treatment. Similarly, the representative drugs that proved beneficial to alleviate SARS‐CoV‐1, MERS‐CoV, HIV, ZIKV, H1N1, and malarial infection in the past presented a sturdy candidature for ameliorating the COVID‐19 therapeutic doctrine. However, most of the deliberations for developing effective pharmaceuticals proved inconsequential, thereby encouraging the identification of new pathways, and novel pharmaceuticals for capping the COVID‐19 infection. The COVID‐19 contagion encompasses a burst release of the cytokines that increase the severity of the infection mainly due to heightened immunopathogenicity. The pro‐inflammatory metabolites, COX‐2, cPLA2, and 5‐LOX enzymes involved in their generation, and the substrates that instigate the origination of the innate inflammatory response therefore play an important role in intensifying and worsening of the tissue morbidity related to the coronavirus infection. The deployment of representative drugs for inhibiting these overexpressed immunogenic pathways in the tissues invaded by coronaviruses has been a matter of debate since the inception of the pandemic. The effectiveness of NSAIDs such as Aspirin, Indomethacin, Diclofenac, and Celecoxib in COVID‐19 coagulopathy, discouraging the SARS viral replication, the inflammasome deactivation, and synergistic inhibition of H5N1 viral infection with representative antiviral drugs respectively, have provided a silver lining in adjuvant COVID‐19 therapy. Since the anti‐inflammatory NSAIDs and COXIBs mainly function by reversing the COX‐2 overexpression to modulate the overproduction of pro‐inflammatory cytokines and chemokines, these drugs present a robust treatment option for COVID‐19 infection. This commentary succinctly highlights the various claims that support the status of immunomodulatory NSAIDs, and COXIBs in the adjuvant COVID‐19 therapy.

A HOME-TREATMENT ALGORITHM BASED ON ANTI-INFLAMMATORY DRUGS TO PREVENT HOSPITALIZATION OF PATIENTS WITH EARLY COVID-19: A MATCHED-COHORT STUDY (COVER 2)

“…Our recommendation treatment algorithm (17) is based on the idea that it is critical to intervene at home very early on during the onset of mild/moderate symptoms to avoid progression toward severe COVID-19, which would eventually require hospital admission. Indeed, after the initial exposure to SARS-CoV-2, patients typically develop symptoms that indicate an inflammatory process within 5 to 6 days on average (15,16), and pro-inflammatory mediators, in particular cytokines, seem to be integral to the initiation, intensification, propagation and worsening of tissue morbidity related to COVID-19 (16,19,26). Therefore, our recommended treatment algorithm moved from this pathophysiologic rationale of early COVID-19 events, and focused on the initial use of NSAIDs, which has been shown to reduce pro-inflammatory cytokine levels (18).…”

“…NSAIDs inhibit the cyclooxygenase activity of prostaglandin H synthase 1 and 2, also named COX-1 and COX-2 (27). Relatively selective COX-2 inhibitors (e.g., celecoxib, etoricoxib) (27) may reduce pro-inflammatory cytokine levels, as shown in mice with influenza A infection (TNF-α, G-CSF, and IL-6) (28) and in hospitalized COVID-19 patients (IL-6) (19,29). The overlap in COX-2 selectivity between coxibs and the more traditional NSAID nimesulide (27) was the rationale for recommending these drugs for the treatment of early COVID-19 at home, unless contraindicated.…”

“…Over the past two years the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), which causes coronavirus disease 2019 (COVID- 19), has quickly spread globally, reaching pandemic proportions (1). Through genetic evolution resulting in multiple variants (2), SARS-CoV-2 has been responsible for several pandemic waves worldwide (1).…”

Antiviral Properties of the NSAID Drug Naproxen Targeting the Nucleoprotein of SARS-CoV-2 Coronavirus

“…SARS-CoV-2 infection also upregulates COX-2 in human cell culture and mouse models [ 7 ]. The effectiveness of COX-1/COX-2 inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen and celecoxib, discouraging the inflammasome activation could limit the cytokine storm [ 8 ]. Although it was initially suggested that NSAIDs could increase ACE2 receptor expression, thereby possibly promoting viral entry, a recent clinical trial attested the safety of COX-2 inhibitors and suggested their ability to reduce IL6 levels [ 9 ].…”

Indomethacin for refractory COVID or post-COVID headache: a retrospective study

“…Drugs with potential for inhibiting these overexpressed immunogenic pathways in the tissues invaded by coronaviruses has been a matter of debate since the inception of the pandemic. The effectiveness of NSAIDs such as Indomethacin in COVID-19 coagulopathy, discouraging the SARS viral replication, the inflammasome deactivation, and synergistic inhibition of H5N1 viral infection with representative antiviral drugs, have provided a silver lining in adjuvant COVID-19 therapy [ 30 , 31 ].…”