Potential treatment and prophylactics in COVID-19
Despite recent advancements in technology, the prevention/treatment for COVID-19 is still unpredictable, where many factors are involved in finding prophylaxis or treatment. Whether mitochondria could be a potential target in treating the COVID-19 disease is still a very premature question. However, based on existing literature, strong evidence, and manipulation of mitochondrial function by SARS-CoV-2, it is apparent that mitochondria are a potential target in COVID-19 treatment. Hence, improving mitochondrial function could by any means be detrimental to virus establishment. Therefore, when concerning the mitochondria, treatment options can include compounds that modulate mitochondrial bioenergetic functions as the virus relies on energy from the mitochondria. On the other hand, virus-induced mitochondrial dysfunction could be alleviated by increasing mitochondrial function by employing mitochondrial modulators, thereby preventing mitochondrial hijacking by the virus. Although vaccines are the ultimate prophylactic option, the development of multiple vaccines for SARS-CoV-2 is actively underway at a rapid rate, with numerous potential candidates and involving various strategies (RNA, DNA, proteins and antibodies).
While most of the other proposed, practicing treatments vary between the demographics, no one possible strategy is favorable currently. It is unclear because it has not been studied whether these strategies involve direct or indirect mitochondrial manipulation. On the other hand, potential drugs are antiviral drugs previously developed for other coronaviruses. Some of them include Lopinavir and Ritonavir, which are HIV protease inhibitors that have proven to be effective against SARS-CoV in vitro and in studies involving non-human primates infected with the Middle East respiratory syndrome-CoV (MERS-CoV) (Chan et al., 2015; Chu et al., 2004). However, they did not show efficacy or a faster recovery time in patients with COVID-19 (Cao et al., 2020a; Yang, Tekwani & Martin, 2020). On the other hand, the FDA approved Remdesivir, a nucleoside analog, has shown to be effective against SARS-CoV and MERS-CoV in vitro (Agostini et al., 2018; Sheahan et al., 2020). However, there is insufficient strong clinical evidence proving its effectiveness against COVID-19. Nevertheless, this regimen is shown to decrease the hospitality rate and improve the discharge rate compared to the placebo, and it has also displayed a shortened recovery time in COVID-19 patients (Beigel et al., 2020; Paladugu & Donato, 2020). However, their role in influencing mitochondrial function is not known.
In addition, a class of anti-malarial drugs, chloroquine (CQ) and hydroxychloroquine (HCQ) have been shown to inhibit SARS-CoV and CoV-2 establishment in vitro (Vincent et al., 2005; Wang et al., 2020). Since then, multiple clinical trials have been initiated to study the effects of these anti-malarial drugs on COVID-19 disease and it is getting controversial as only one report showed a beneficial effect (Gao, Tian & Yang, 2020). There are many proposed theories that CQs inhibit cellular entry of the virus, including by inhibiting lysosomal uptake (Hashem et al., 2020; Mauthe et al., 2018). However, the effects of CQs on mitochondrial function are not so intensively investigated, but it has been shown that CQ inhibits mitochondrial respiration, ATP production and function (Deepalakshmi, Parasakthy, Shanthi & Devaraj, 1994; Redmann et al., 2017) and whether this influence the treatment is not clear. When ACE-2 was identified as the primary mediator for SARS-CoV and CoV-2 entry, small molecule and peptide inhibitors of ACE-2, recombinant proteins, and phytoconstituents were being actively investigated as a potential treatment for COVID-19. However, their outcomes are not clear as well (Guy, Jackson, Jensen, Hooper & Turner, 2005; Han, Penn-Nicholson & Cho, 2006; Monteil et al., 2020; Mores, Matziari, Beau, Cuniasse, Yiotakis & Dive, 2008; Pedersen, Sriramula, Chhabra, Xia & Lazartigues, 2011; Trask et al., 2010; Ye et al., 2012).
On the other hand, melatonin also emerges as one of the potential enhancers in COVID-19 treatment (Zhang et al., 2020). As evidence suggests that melatonin is synthesized in mitochondria, the protective effect of melatonin is also proposed and shown (Tan, Manchester, Qin & Reiter, 2016). Melatonin is shown to improve mitochondrial function by increasing oxidative phosphorylation and ATP production in addition to upregulating antioxidant enzymes, scavenging ROS, and RNS (Absi, Ayala, Machado & Parrado, 2000; Bromme, Morke, Peschke, Ebelt & Peschke, 2000; Ding et al., 2014; Jou et al., 2007; Kilanczyk & Bryszewska, 2003). Therefore, it is possible that melatonin treatment may potentiate and improve outcomes in COVID-19 treatment. But, whether all these regimens affect mitochondrial function in preventing SARS-CoV-2 infection needs to be explored.