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.