Working Hypothesis: Three distinct mechanisms by which PAK1-blockers interfere with COVID-19-induced fibrosis.

Hiroshi Maruta, PAK Research Center, Melbourne, Australia. e-mail: Maruta20420@yahoo.co.jp ABSTRACT: According to our previous 2020 mini-review in Med. Drug Discov. (1), there are at least “two” distinct mechanisms by which PAK1-blockers such as propolis, ivermectin, and vitamin D3 could interfere with COVID-19-induced fibrosis: (i) promoting immune system to produce antibodies against this RNA virus, and (ii) inhibiting COVID-19-induced inflammation of lungs (fibrosis) which involves ACE2-PAK1-CCL2 signaling pathway. In this article, I shall add a “third” mechanism which directly blocks the viral entry into the host cells. This is based on cell culture study in a 2018 article where Gleevec blocks the viral entry into Vero cells with IC50 ranging 1-10 micro M (2). The primary target of Gleevec is a Tyrosine-kinase called ABL, and its IC50 is around 25 nM (3). However, it also inhibits two other kinases called KIT and PDGFR (receptor for PDGF). If I recall correctly, its IC50 against PDGFR ranges 1-10 micro M, inhibiting the PAK1-dependent growth of A549 lung cancer cells (4). Thus, it is most likely that its anti-viral effect is due to its inhibition of PDGFR, instead of ABL. Furthermore, PDGFR activates PAK1 through EGFR-RAS signalling pathway. According to the 2018 article, Gleevec, a PAK1-blocker, interferes with the viral S protein-cell fusion essential for the viral entry into the host cells (2).
According to another 2020 article, Ivermectin also blocks the replication of COVID-19 in Vero cells (5), and a more recent observation suggests that a few other PAK1-blockers such as CEP (Cepharanthine) also block the viral replication in cell culture with IC50 around 1 micro M (6-8). Most interestingly, CEP and Gleevec share the same target (PDGFR), blocking the down-stream EGFR-RAS-JAK-PAK1 signaling pathway (4,7,8). These in vitro observations altogether with several distinct PAK1-blockers strongly suggest, if not "genetically" proven as yet, that viral replication per se, in particular the viral entry into host cells (virus-cell membrane fusion) requires PAK1. PAK1-requirement for viral entry is not unique to COVID-19, as several other pathogens such as HIV, influenza virus, malaria and H. pylori also require PAK1 for their entry into host cells (1).
References:
1.Maruta H, He H. PAK1-blockers: Potential Therapeutics against COVID-19. Med Drug Discov. 2020 Apr 19; 6:100039.
2. Sisk JM, Frieman MB, Machamer CE. Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors. J Gen Virol. 2018; 99(5):619-630.
3. Thomas O'Hare, Roy Pollock, Eric P Stoffregen, et al. Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML. Blood. 2004;104(8):2532-9.
4. Peilin Zhang, Wei Yi Gao, Steven Turner, Barbara S Ducatman. Gleevec (STI-571) inhibits lung cancer cell growth (A549) and potentiates the cisplatin effect in vitro. Mol Cancer. 2003; 2:1.
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6. Hua-Hao Fan, Li-Qin Wang, Wen-Li Liu, et al. Repurposing of clinically approved drugs for treatment of COVID-19 in a 2019-novel coronavirus-related coronavirus model. Chin Med J (Engl). 2020 May 5;133(9):1051-1056.
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