Abstract
Increasing outbreaks of new pathogenic viruses have promoted the exploration of novel alternatives to time-consuming vaccines. Thus, it is necessary to develop a universal approach to halt the spread of new and unknown viruses as they are discovered. One such promising approach is to target lipid membranes, which are common to all viruses and bacteria. The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has reaffirmed the importance of interactions between the virus envelope and the host cell plasma membrane as a critical mechanism of infection. Metadichol®, a nanolipid emulsion of long-chain alcohols, has been demonstrated as a strong candidate that inhibits the proliferation of SARS-CoV-2. Naturally derived substances, such as long-chain saturated lipid alcohols, reduce viral infectivity, including that of coronaviruses (such as SARS-CoV-2) by modifying their lipid-dependent attachment mechanism to human host cells. The receptor ACE2 mediates the entry of SARS-CoV-2 into the host cells, whereas the serine protease TMPRSS2 primes the viral S protein. In this study, Metadichol® was found to be 270 times more potent an inhibitor of TMPRSS2 (EC50 = 96 ng/mL) than camostat mesylate (EC50 = 26000 ng/mL). Additionally, it inhibits ACE with an EC50 of 71 ng/mL, but it is a very weak inhibitor of ACE2 at an EC50 of 31 μg/mL. Furthermore, the live viral assay performed in Caco-2 cells revealed that Metadichol® inhibits SARS-CoV-2 replication at an EC90 of 0.16 μg/mL. Moreover, Metadichol® had an EC90 of 0.00037 μM, making it 2081 and 3371 times more potent than remdesivir (EC50 = 0.77 μM) and chloroquine (EC50 = 1.14 μM), respectively.
Highlights
There is an increasing need to develop broadspectrum antimicrobial agents that can inactivate human pathogens, such as bacteria and viruses
For all practical purposes, it does not inhibit angiotensin-converting enzyme 2 (ACE2) (Table 7 and Figures 3 and 4) and inhibits transmembrane protease serine 2 (TMPRSS2) which is needed for the virus to bind to angiotensin-converting enzyme (ACE) 2
Inhibition of ACE, a blood pressure regulator, is crucial to mitigate COVID-19 infections, as Guan et al [26] validated that the single highest risk factor in infections is hypertension in 15% of the 1099 COVID-19 patients that participated in the study
Summary
There is an increasing need to develop broadspectrum antimicrobial agents that can inactivate human pathogens, such as bacteria and viruses. Rapid development of antimicrobial resistance in microorganisms has propelled the development of targeted drugs. The most recent trigger is the fear of a future pandemic caused by poorly studied novel virulent strains, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing COVID-19 pandemic caused by SARS-CoV-2 [1] has created global havoc within a few months of its emergence. The SARS-CoV-2 virus enters a host cell by interacting with the transmembrane protease serine 2 (TMPRSS2) [3], a serine protease, and the angiotensin-converting enzyme 2 (ACE2) present on the host cell [4]. Inhibiting TMPRSS2 is the key to blocking the virus from binding to ACE2, hindering the mechanism underlying its entry into the host cell
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