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EvolVeritas developed the first efficient method for producing wildtype, fully active TMPRSS2 protease, which facilitates their anti-influenza and anti-coronavirus drug development program
Summary: Viral infections cause serious health, economic and social damage worldwide. Vaccination using viral proteins, inactivated virions or modified RNA is essential to combat pandemia, but it has several limitations. One is that the viral proteins rapidly evolve. EvolVeritas pursues a different strategy. It targets non-evolving human proteins that are essential for certain viruses to infect the human cells. An important example is human TMPRSS2, which is a key host protease that facilitates the infections of several coronaviruses and influenza viruses. In their recent publication published in the Biochemical Journal, the researchers of the EvolVeritas Ltd. report the first method enabling the production of the wildtype form of fully active TMPRSS2 protease. This will speed up their novel drug development programs to prevent and treat coronavirus and influenza virus infections through highly potent and highly selective TMPRSS2 inhibitors.
Coronaviruses, such as SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E use their spike (S) protein, while influenza viruses use their hemagglutinin protein to bind to certain receptor proteins on the human cell surface. The membrane-bound human protease, TMPRSS2 cleaves the S protein or the hemagglutinin protein allowing for an efficient fusion of the viral envelope with the human cell membrane facilitating the entry of the viral genetic material into the cell. Inhibition of TMPRSS2 is a promising strategy for the prevention and treatment of coronavirus and influenza virus infections. Consequently, TMPRSS2 is an attractive therapeutic target.
So far, drug development efforts have been significantly hampered by the lack of adequate amounts of pure, highly active recombinant TMPRSS2. Previously published methods provided mutant TMPRSS2 with low enzymatic activity and insufficient quantity. These methods failed, because highly active TMPRSS2 damaged the cell and also degraded itself before reaching the cell surface.
The method developed by EvolVeritas is based on the simultaneous expression of the protease and its natural inhibitor HAI-2. There are two key elements of the newly developed method. One is that the proteolytic activity of TMPRSS2 is kept under control inside the cell by HAI-2. The other key element of the EvolVeritas method is secreting the active protease into the medium, while withholding the HAI-2 inhibitor as an integral membrane protein of the cell. This way TMPRSS2 can be easily separated from the cells and the cell-bound inhibitor, and purified to homogeneity.
The EvolVeritas researchers managed to produce large quantities of ultra-pure recombinant TMPRSS2. The activity of the recombinant ectodomain far exceeds the activity of the proteases produced by other methods. They applied the same method for recombinant expression of related membrane proteases, such as TMPRSS13.
TMPRSS13 is also an important drug target protein: it not only participates in viral infections, but is also involved in carcinogenesis. With the purified recombinant proteases the EvolVeritas scientists clarified the mechanism of zymogen activation. They showed that TMPRSS2 is highly prone to autoactivation, but cross-activation of the zymogen by a related membrane protease is also a possible scenario.
Solving the problem of active TMPRSS2 and TMPRSS13 production opened new frontiers for developing novel antiviral drugs.
The drug candidate of EvolVeritas may provide protection against organ damage linked to transplantation, heart attack, and stroke
Summary: The unique lead molecule of the Hungarian pharmaceutical start-up company EvolVeritas, EVO24L, protects the body from tissue damage following oxygen deprivation. When a vessel is blocked, due to organ transplantation, heart attack, or stroke, the affected organ suffers from oxygen deprivation, and the cells display distress signals on their surface. Although blood supply can be restored surgically or by medication, this also initiates a process called reperfusion injury. The reason for this is that along with the blood providing oxygen and nutrients, immune proteins also arrive to the affected tissue recognizing the distress signals and triggering organ damage. EvolVeritas’ patented drug candidate prevents this by selectively inhibiting the harmful component of the immune response. EVO24L has proven effective in animal experiments. The breakthrough result was published in the prestigious journal PNAS.
EvolVeritas was founded by researchers-inventors from the Faculty of Natural Sciences at Eötvös Lorand University and the HUN-REN Research Centre for Natural Sciences. Under the leadership of Gábor Pál and Péter Gál, the company developed a unique drug candidate through the directed evolution of a human protein. The patented EVO24L prevents organ damage that inevitably occurs following oxygen deprivation. When an organ suffers from oxygen deprivation due to vessel blockage, such as in organ transplantation, heart attack, or stroke, the cells display distress signals on their surface. Although blood supply can be restored with thrombolytic medication or catheter treatment, with the fresh blood providing oxygen and nutrients, immune proteins that recognize the distress signals also arrive. One of them, the MASP-2 protease, initiates an avalanche-like
inflammation, leading to life-threatening organ damage.
EvolVeritas’new active molecule, EVO24L, prevents the development of inflammation and tissue damage by perfectly and permanently blocking the active site of MASP-2. The EVO24L drug candidate was tested by an Australian research group specializing in kidneys. They used an animal model specifically designed to study organ damage due to oxygen deprivation accompanying kidney transplantation. In their study, the kidney function of the placebo-treated individuals collapsed, while the kidney function and tissue of the EVO24L-treated animals remained intact. The breakthrough result was published in the prestigious journal of the National Academy of Sciences of the United States, PNAS.
EvolVeritas aims to develop a drug that will be widely applicable to prevent organ damage during and after organ transplantation, heart attack, and stroke. The spin off company, founded by the inventors from the joint research of ELTE FNS and HUN-REN RCNS, develops, through directed protein evolution, ultra-selective drug molecules that prevent or alleviate inflammation; SARS-CoV-2 and influenza virus infections and they are business discussions with the world’s leading pharmaceutical manufacturers and pharmaceutical investors for their further development towards drugs that address unmet medical needs.