J.
Infectious Diseases & Therapy (2020): 8 (2) 418.
Hiroshi Maruta ,
PAK Research Center, Melbourne, Australia
Abstract:
The following
are two major scientific evidences for PAK1-dependency of coronaviral infection:
(i) A tumor suppressor phosphatase called PTEN, which inactivates PAK1,
suppresses the coronavirus-induced CCL2-dependent fibrosis of lungs, and (ii) CCL2
expression depends on coronaviral receptor called ACE2 (angiotensin converting
enzyme 2) –CK2/RAS-PAK1-RAF-AP1 signaling pathway. Accordingly, in principle, the
following several PAK1-blockers readily available in the market could be potentially
useful for the treatment of coronaviral infection: a bee product called
propolis, Melatonin from pineal glands, Ivermectin, Triptolide from thunder god
vine (a Chinese traditional medicine), and an old pain-killer called Ketorolac.
Alternatively, since coronavirus, an RNA virus, requires RNA-dependent RNA
polymerase (RdRP) for its replication, a series of its synthetic inhibitors
such as Remdesivir would also be useful for tackling this pandemic virus.
Commentary
Among
the several chemical drugs that they tested against coronaviral infection in
cell culture, an old malaria drug called Chloroquine (CQ) and Remdesivir that
inhibits RNA-dependent RNA polymerase (RdRP) appear to be the most potent with
IC50 around 1 mM. Unfortunately,
however, mainly due to its side effects and drug-resistance, CQ is no longer
used for malaria therapy at least in US, Europe and Japan. However, a few other
new anti-malaria chemicals such as Arteminisin (AM), which was developed by
Youyou Tu in China, a 2015 Nobel laureate and Hydroxychloroquine (HQ) are in
the market for malaria therapy.
The
following are two major scientific evidences for PAK1-dependency of coronaviral
infection: (i) Very recently a team at Colorado University found that a tumor
suppressor phosphatase called PTEN, which inactivates PAK1, suppresses the
coronavirus-induced CCL2-dependent fibrosis of lungs (3), and (ii) a decade ago
a team in Taipei found that CCL2 expression depends on coronaviral receptor
called ACE2 (angiotensin converting enzyme 2) –CK2/RAS-PAK1-RAF-AP1 signaling
pathway (4, Fig. 1).
In
addition to the above anti-malaria drugs, there are several natural or
synthetic PAK1-blockers which are readily available in the market: a bee
product called propolis, Melatonin from pineal glands, Ivermectin, Triptolide
from thunder god vine (a Chinese traditional medicine), an old pain-killer called
Ketorolac and so on (5). In addition, these PAK1-blockers stimulate antiviral
immune systems (Ab production) in hosts which are normally suppressed by PAK1
(6). Thus,
they
would be potentially better than its vaccine alone. I hope the WHO, NIH and other
medical officials take this outsider’s wisdom for a tip to tackle or ease the
current pandemic corona-virus outbreaks, before its specific vaccine becomes
available in the end.
Alternatively,
since a group at Alberta University in Canada also confirmed that an ATP analog
called Remdesivir or GS-5734 which selectively inhibits RNA-dependent RNA
polymerase (RdRP) derived from this RNA virus is also effective to suppress its
replication (7), NIH has recently started the clinical trials of Remdesivir for
COVID-19 patients. GS-5734 was originally developed for the potential treatment
of Ebola virus in 2019 by Gilead Sciences in California (7).
More recently,
another PAK1-blocker called Ivermectin developed by Nobel-laureates (Satoshi
Omura and Willey Campbell) in 1980s was also proven to block COVID-19 infection in cell culture with IC50 around 2.5 micro M.
A PAK1-blocking glucocorticoid
hormone called “Ciclesonide”, which has been used to treat mainly asthma,
was recently shown to ease the COVID-19 pathogenesis clinically: https://writening.net/page?FC3QPm
References:
1. Maruta
H. (2014). Herbal therapeutics that block the oncogenic kinase PAK1: a
practical approach towards PAK1-dependent diseases and longevity. Phytother
Res. 28, 656-672.
2.
Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. (1994) A brain
serine/threonine protein kinase activated by Cdc42 and Rac1 (PAK). Nature. 367 (6458),
40-46.
3.
Lu S, Strand KA, Mutryn MF, et al (2020). PTEN (Phosphatase and Tensin Homolog)
Protects Against Ang II (Angiotensin II)-Induced Pathological Vascular Fibrosis
and Remodeling-Brief Report. Arterioscler Thromb Vasc Biol. 40, 394-403.
4.
Chen IY, Chang SC, Wu HY, et al (2010). Upregulation of the chemokine (C-C
motif) ligand 2 (CCL2) via a severe acute respiratory syndrome coronavirus
spike-ACE2 signaling pathway. J Virol. 84, 7703-7712.
5.
Maruta H, Ahn MR. (2017). From bench (laboratory) to bed (hospital/home): How
to explore effective natural and synthetic PAK1-blockers/Longevity-promoters
for cancer therapy, Eur. J. Med. Chem. 142, 229-243.
6.
Huynh N, Wang K, Yim M, et al. (2017). Depletion of p21-activated kinase 1
(PAK1) up-regulates the immune system of APC∆14/+ mice and inhibits intestinal
tumorigenesis. BMC Cancer. 17, 431.
7. Gordon
CJ, Tchesnokov EP, Feng JY, et al (2020). The antiviral compound remdesivir
potently inhibits RNA-dependent RNA polymerase from Middle East respiratory
syndrome coronavirus. J Biol Chem. pii: jbc.AC120.013056.
For detail of PAK1-blockers readily available in the market:
PAK1-blockers: Potential Therapeutics against
COVID-19.
