2020年2月3日月曜日

A Letter to New York Times (2020) :
"PAK1-blockers" against Coronaviral Pandemic


Currently, Coronavirus-based infection (over 1,800,000 people) caused a global threat to our health. Far worse than the Sars virus calamity in 2003 (the death toll over 90,000 people), it causes the deadly fibrosis (inflammation) in our lungs. WHO and other medical officials rather naively believe that its only effective therapy is its specific "vaccine". However, it would take at least 12 months (realistically 18 months) to prepare it. In other words, most of the current coronavirus patients would perish until then.

Vaccine therapy of pathogenic viruses or bacteria is based on a very old approach developed by Louis Pasteur (1822-1895) in mid-19th century. Thereafter the chemotherapy of infectious diseases was established by Paul Ehrlich (1854-1915) in 1909 with Salvarsan (606) against Syphilis etc. Towards the end of WWII, antibiotics called Penicillin and PAS (para-amino salicylate) were also developed for therapy of TB and other bacterial infections.

Around the end of 20th century, a unique “pathogenic” kinase called PAK1 (RAC/CDC42-activated kinase 1) was cloned in mammals by Ed Manser in Singapore (1). This kinase turned out to be very similar to a “myosin kinase” that we isolated at NIH from a soil amoeba around 1977 (2). Since then we and a few other teams found that PAK1 is responsible for cancers, ageing processes and a wide variety of other diseases including bacterial and viral infections caused by influenza virus, HIV, papilloma virus, malaria etc (3). Furthermore, PAK1 contributes to the suppression of both B-cell and T-cell based immune systems (4).

Very recently, a group at University of Colorado found that coronavirus-based CCL2-dependent lung fibrosis was blocked by a tumor suppressor called PTEN, a phosphatase which inactivates the oncogenic PAK1 (5).  Furthermore, a
decade ago, a group at Taipei found that expression of CCL2 in lung cells depends on the oncogenic signalling pathway including trans-membrane viral receptor called ACE2 (Angiotensin-converting enzyme 2), kinases CK2, PAK1, RAF and the transcription factor AP-1 (6, see Fig. 1). Thus, it is most likely that PAK1-blockers (natural or synthetic) such as propolis, Ivermectin, ATRA (all-trans retinoic acid), melatonin and Ketorolac, an old pain-killer, readily available in market (3) could be effective therapeutics for prevention and cure of coronavirus infection, instead of its specific vaccine.

Moreover, back in 2006, a team at University of Rome reported that another old pain-killer called Indomethacin, a COX-2 inhibitor, suppresses the sars and corona virus infection in dogs with 1 mg/kg/day (7). Interestingly, COX-2 expression depends on the oncogenic PAK1.

In conclusion, I would urge the WHO, NIH and other world medical (infectious disease) institutions to consider the instant PAK1-blocking therapy of the deadly corona virus infection in China and other countries, before its (old-fashioned) vaccine becomes available in the end.

https://steemkr.com/health/@pomeline/ivermectin-a-possible-treatment-of-coronaviruses-and-ncov

Warmest regards,

Prof. Hiroshi Maruta
PAK Research Center,
Melbourne, Australia.


References:

1.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.

2. Maruta, H., Korn ED. (1977) Acanthamoeba cofactor protein is a heavy chain kinase required for actin activation of the Mg2+-ATPase activity of Acanthamoeba myosin I. J Biol Chem. 252, 8329-8332.

3. 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.

4. 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.

5. 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.

6. Chen IY, Chang SC, Wu HY, et al (2010). Upregulation of the chemokine (C-C motif) ligand 2 via a severe acute respiratory syndrome coronavirus spike-ACE2 signaling pathway. J Virol; 84: 7703-7712.

7.Amici C, Di Caro A, Ciucci A, et al (2006). Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir Ther. 11: 1021-1030.

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