key: cord-0774155-zd6e32rl
authors: Danta, Chhanda Charan
title: CNS Penetration Ability: A Critical Factor for Drugs in the Treatment of SARS-CoV-2 Brain Infection
date: 2020-07-08
journal: ACS Chem Neurosci
DOI: 10.1021/acschemneuro.0c00335
sha: e4504200cd45f51eca63ceff61f407fd062ce38f
doc_id: 774155
cord_uid: zd6e32rl

Now, it has been evidenced that Covid19 (SARS-CoV-2) infects the brain tissues. Along with this, a challenge has been raised for research professionals to find effective drugs for its treatment since the recent spread of this virus from Wuhan, China. Targeting the treatment of brain infection, it has also been a challenge that the clinical drug should have good CNS penetration ability to cross the blood–brain barrier.

F ollowing the early evolutionary history of coronaviruses, it has been determined that the novel COVID19 coronavirus is homologous (based on genome sequence analysis) to human coronaviruses such as severe acute respiratory syndrome (SARS-CoV) and the Middle East respiratory syndrome (MERS-CoV). All coronaviruses are zoonotic pathogens possessing singlestrand RNA as their genetic material. Furthermore, following their clinical symptoms of infections in the human body, it was found to be similar. The COVID19 coronavirus not only causes infection of the respiratory and gastrointestinal systems but also causes infection of brain tissues. 1 It has been reported that COVID19 uses spike (S) protein to enter into host cells through the angiotensin-converting enzyme 2 (ACE2) receptors. The ACE2 receptors are expressed and distributed well in brain cells, so they allow chances for brain infections. 2 The experiment carried out by Netland et al. 3 in transgenic mice showed that SARS coronavirus infections caused neuronal death. This experiment demonstrated that the virus enters the brain primarily through the olfactory bulb, and the infection spread rapidly to trans-neurons and then to connected areas of the brain. The extensive neuronal infection was the main cause of death. Importantly, it was also noticed that intracranial inoculation with low doses of virus resulted in a uniformly lethal disease. They found that the death of mice was due to the death of infected neurons located in cardiorespiratory centers in the medulla. Furthermore, the virus induced minimal cellular infiltration in the brain. These results revealed that SARS-CoV can potentially target neurons. 3 Recently, the neuroinvasive and neurodegeneration-like potential of COVID19 are well reported. 1, 4 Therefore, it has become urgent to think about the screening of potential drugs (Figure 1 ) for the treatment of COVID19 CNS infections.

Earlier clinical reports suggested that drugs used for the treatment of viral CNS infections showed poor CNS penetration abilities and therefore exhibited lower CSF concentrations and were unable to inhibit or stop viral RNA replication. 5 Chemical structure analysis of those drugs revealed that they possessed lower log P values (the critical factor for CNS penetration) and hence were unable to cross the BBB. The low log P value of some drugs is due to the presence of more polar atoms such as O, N, S, P, F, etc. in functional groups. A list of drugs ( Table 1 ) that are currently under clinical trial or in the pipeline for the treatment of COVID19 infection has been summarized. 6, 7 The chemical structures were drawn and the log P value was calculated using an in silico tool. Ideally, according to Lipinski's rule of 5, a log P value less than 5 is useful for a pharmacologically effective drug. 7 Most probably, this information would be highly useful for the biologists in screening drugs, for physicians to select drugs for their prescriptions, and for medicinal chemists to further design potential antiviral drugs targeting the effective treatment of COVID19 CNS infection. 

United Kingdom; Email: ccdanta2011@ rediffmail

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