In January 2020, the World Health Organization (WHO) issued a statement, declaring the outbreak of the new coronavirus (COVID-19), which has become the sixth leading cause of public health emergencies worldwide. Severe acute respiratory syndrome coronaviruses (SARS-CoV) are a large group of viruses that can infect animals and humans, which cause respiratory distress (Corouble et al., 2021; Rizwanetal.,2021; Seif et al., 2020). Given a high mortality rate of ∼3.7%, compared to an influenza-related death rate of <1%, search for anti-COVID-19 remedies and neutralizing vaccines is urgently required. The hyperinflammatory phenomenon of ‘cytokine storms’ appears to play a crucial role in severe cases who suffered from COVID-19. According to a Lancet correspondence, some patients suffering from severe COVID-19 are subject to cytokine storm syndrome, and patients who die in intensive care units (ICUs) are more likely to experience an adverse reaction from their immune systems than from the virus (Mehta et al., 2020).
Conferring to another study, the incubation period of the coronavirus, the duration between the time of infection and the appearance of the first symptoms would be five days on average. Infection with COVID-19 in the early stages is associated with non-specific and general symptoms. COVID-19 patients have shown abnormally high levels of several cytokines in the blood/serum, which lead to a high mortality rate due to complications.
On the other hand, metronidazole (MTZ) is a nitroimidazole group antibiotic with the ability to treat infectious diseases (Brogden et al., 1978), as well as COVID-19 (Gharebaghi et al., 2020a; Kotta et al., 2020 ; WHO, 2021). A new study shows that the administration of MTZ to COVID-19 patients resulted in a significant reduction in cytokines (Gharebaghi et al., 2020b). In general, IL-12 is an important cytokine for steering the immune system toward a Th1 response and avoiding a Th2 immunological profile. As a result, while IL-12 is critical in the defense against some pathogens, namely intracellular pathogens, excessive production of this cytokine is implicated in the pathogenesis of several inflammatory and autoimmune illnesses.
However, the main drawback of such a study or the previous statements about the anti-inflammatory effects of MTZ for COVID-19 patients is that its mechanism of action and interactions with cytokines are unknown so far. In silico methods such as molecular docking-based binding studies between macromolecules and drugs have been a lucrative choice in recent days. Thus, the current study aimed to identify anti-cytokine therapeutics for the treatment of COVID-19 patients with cytokine storm.
Materials and methods
The interaction of MTZ with key cytokines was investigated using molecular docking studies. IL-12–metronidazole complex is found to be more stable than all other cytokines under study. Our study also revealed that the active sites of IL-12 are inhibited from binding to its target, IL-12 receptor, by modifying the position of the methyl and hydroxyl functional groups in MTZ. Three MTZ analogues, metronidazole phosphate, metronidazole benzoate, 1-[1-(2-Hydroxyethyl)-5-nitroimidazol-2-yl]-N-methylmethanimine-oxide, and two FDA-approved drugs acyclovir (ACV), and tetrahydrobiopterin (THB) were also found to prevent binding of IL-12 to IL-12 receptor similar to MTZ by changing the surface and volume of IL-12 upon IL-12-drug/ligand complex formation. According to the RMSD results, after 100 ns MD simulations of human IL-12-MTZ/ACV/THB drug complexes, it was also observed that each complex was swinging within a few Å compared to their corresponding docking poses.
Conclusion
This biomolecular docking study demonstrates that three FDA-approved drugs, namely, metronidazole, acyclovir and tetrahydrobiopterin, are potential repurposable treatment options for overexpressed serum cytokines found in COVID-19 patients. Similar approach is also useful to develop therapeutics against other human disorders.
Author: Hendrik Setia Budi
Details of the research can be viewed here:
Bahareh Farasati Jauh, Dmitry Bokov, Gunawan Widjaja, Hendrik Setia Budi, Walid Kamal Abdelbasset, Shahrzad Javanshir, Farhad Seif, Hamidreza Pazoki-Toroudi , Sanjay Kumar Dey . Metronidazole, acyclovir and tetrahydrobiopterin may be promising to treat COVID-19 patients, through interaction with interleukin-12. Journal of Biomolecular Structure and Dynamics. 2022 Apr 21:1-19. doi : 10.1080/07391102.2022.2064917
