Targeting the BEST SUPPORTING ACTOR for COVID-19 Treatment

The novel coronavirus that entered our lives under the name SARS-COV-2, and against which we have been struggling for some time, causes COVID-19 disease and endangers the lives of millions of people regardless of age. Clarifying the virus's life cycle is very important for scientists working to understand and prevent the disease. The scientific community is devoting all its efforts to investigating the virus's activity at the cellular level. Answering key questions – which cells in our bodies the novel coronavirus can attach to, which receptors it recognizes while attaching, and which activities it performs in sequence after entering a cell – gives us a major advantage in vaccine and drug development. If we can understand and explain these points, we can develop drugs that block the virus's vital functions and predict the harm it may cause in the human body.

The Entry Gate: ACE2 Receptors

One of the earliest things we learned about the novel coronavirus was its entry gate. Initial studies, shortly after the virus was identified, showed that SARS-COV-2 attaches to special cell-surface receptors called ACE2 (Angiotensin Converting Enzyme 2) to enter the cells it will infect, evading our immune cells as it enters. Because our immune system has never encountered this virus before, it cannot recognize it or produce a ready response; it seems not to know what to do…

SARS-CoV-1, another coronavirus that caused SARS (Severe Acute Respiratory Failure) when it emerged in 2002, was also known to use the same entry gate. Comparative experiments, however, showed that the novel coronavirus could attach to ACE2 receptors 10 times more strongly. Our cells with large numbers of ACE2 receptors on their surfaces, and the organs to which these cell groups belong – the lungs, heart, kidneys, blood vessels and intestines – are therefore at risk of involvement. The lungs are the organ with the most ACE2 receptors.

The Best Supporting Actor: Code Name TMPRSS2

We have a group of enzymes that help the virus's attachment arm, the spike protein (S protein), attach to ACE2 receptors in our cells and enter the cells: serine protease enzymes. The particular group that helps SARS-COV-2 is called ‘Serine Protease TMPRSS2’. TMPRSS2 acts primarily as a cleaving enzyme; by cleaving the viral S protein, it allows the viral membrane and host-cell membrane to fuse. Recent studies identifying this enzyme and clarifying the entry mechanism in detail led scientists to ask new questions: ‘Which of our cells contain both the ACE2 receptor and the TMPRSS2 enzyme?’ and ‘If we block the TMPRSS2 enzyme's activity, can we prevent the virus from entering our cells?’

Detailed research prompted by these questions showed that cells containing both the ACE2 enzyme and the TMPRSS2 enzyme are distributed within a fairly limited range. These cells consist mainly of specialized cell groups in our respiratory and intestinal systems. Goblet cells, whose main function is mucus secretion and which are located throughout much of the respiratory system; type-2 pneumocytes in our lungs, responsible for an important secretion called surfactant; and a specific subgroup of enterocytes in the small intestine, responsible for nutrient absorption, contain both ACE2 and TMPRSS2 enzymes and are listed as the most likely and susceptible cell groups for the virus to inhabit.

An Agent Against TMPRSS2

The lack of a drug that can stop the SARS-COV-2 virus from multiplying rapidly after entering our bodies and progressing by attaching to our cells, thereby slowing the worsening course of the disease, means that this highly contagious virus causes new cases and more deaths every day. The TMPRSS2 enzyme, which plays a key role in the virus's entry into cells, is also a target of intensive drug-discovery research and the molecules being tested.

A recent article published in Cell by a group of scientists working in Germany demonstrated the activity of ‘camostat mesylate’, a clinically used protease inhibitor targeting the TMPRSS enzyme. Tested on SARS-COV-2 viruses isolated from a patient, the molecule was reported to prevent viral entry into cells. Important conclusions included the possibility that camostat mesylate could prevent COVID-19 disease from developing in infected people and that it should therefore begin testing in clinical trials. Clinical studies have begun to assess its use for COVID-19; the molecule is already approved in Japan for treating pancreatitis (inflammation of the pancreas).

Camostat Mesylate and the First Human COVID-19 Trials

The first trials began on March 31, 2020 at Aaruhus University in the Danish city of Aaruhus. Camostat mesylate, undergoing phase-I and phase-II studies there, is planned to be tested in a randomized manner in approximately 180 patients. We hope that the clinical trial, whose early results together with long-term findings are expected in December 2020, will produce beneficial results for many patients.

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