X-ray examination identifies compounds that block the main enzyme of the coronavirus

X-ray examination identifies compounds that block the main enzyme of the coronavirus

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Three natural compounds found in foods such as green tea, olive oil and red wine are promising candidates for drug development against the coronavirus. In a comprehensive evaluation of a large library of natural substances in DESY’s PETRA III X-ray source, the compounds bound to a core enzyme vital for coronavirus replication. All three compounds are already used as active substances in existing medicines, as the team led by Christian Betzel from the University of Hamburg and Alke Meents from DESY reported in the journal. Communications Biology. However, whether and when a corona drug based on these compounds can be developed remains to be studied.

“We tested 500 substances from the Karachi Natural Compound Library to see if they bind to the novel coronavirus papain-like protease, which is one of the main targets of an antiviral drug,” explains study lead author Vasundara Srinivasan. . from the University of Hamburg. “A compound that binds to the enzyme in the right place can prevent it from working. »

Papain-like protease (PLPro) is a vital enzyme for virus replication: when the coronavirus hijacks a cell, it is forced to produce building blocks for new virus particles. These proteins are made in the form of a long chain. IT ISPro it then acts like a pair of molecular scissors, cutting the proteins from the chain. If this process is blocked, the proteins cannot assemble new virus particles.

“However, P.L.Pro it has another vital function for the virus,” says Srinivasan. “It blocks an immune system protein, called ISG15, which severely weakens the cell’s self-defense. With PL inhibitorPro we can also enhance the immune response of the cell. »

For experiments, PLPro it was mixed with each of the 500 natural substances in a solution, giving them a chance to bind to the enzyme. It is not possible to see if a substance binds to the enzyme with a conventional light microscope. Instead, small crystals were grown from the mixtures. When illuminated by the bright X-rays from PETRA III on Experiment Station P11, the crystals produce a characteristic diffraction pattern from which the structure of the enzyme can be reconstructed down to the level of individual atoms. “From this information, we can produce three-dimensional models of the enzyme with atomic resolution and see if and where a substance binds to it,” says Meents.

The screening showed that three phenols bind to the enzyme: hydroxyethylphenol (YRL), isolated for the henna tree experiments. lawsonia alba, is a compound present in many foods such as red wine and virgin olive oil and is used as an antiarrhythmic agent. Hydroxybenzaldehyde (HBA) is a known antitumor agent and accelerates wound healing. It was isolated from the copper foil. acalifa cake. Methyldihydroxybenzoate (HE9), isolated from French marigold Tagetes patulaIt is an antioxidant with anti-inflammatory effect and is found in green tea.

In later laboratory tests, established and carried out by Hévila Brognaro in Betzel’s group, the three phenols reduced the activity of PLpro by 50-70% in living cells. “The advantage of these substances is their proven harmlessness,” says Betzel, who is also a member of the CUI center of excellence: Advanced Imaging of Matter. “These compounds are naturally present in many foods. However, drinking green tea will not cure your corona infection! As if it didn’t heal your wounds or cure your cancer. Whether and how a corona drug can be developed from these phenols is a subject for further study. . »

In a different evaluation, a team made up largely of the same scientists had already evaluated thousands of existing drugs in PETRA III as potential inhibitors of the main coronavirus protease (MPro), also a pair of molecular scissors and an important potential drug target. The evaluation identified several corona drug candidates, with the most promising entering preclinical testing. “The corona initiative of DESY and the University of Hamburg is one of the few in the world that has investigated the two main targets of Covid-19,” emphasizes Betzel.

In the new study, scientists from the University of Hamburg, the University of Sao Paulo in Brazil, Diamond Light Source in the UK, European XFEL, Bahauddin Zakariya University in Pakistan, Hospital Israelita Albert Einstein in Brazil, the Pasteur Scientific Platform in Brazil, the European Molecular Biology Laboratory in Hamburg, the Fraunhofer Institute for Translational Medicine and Pharmacology in Hamburg, the Jozef Stefan Institute in Slovenia, the Center of Excellence for Integrated Approaches in Protein Chemistry and Biology in Slovenia, the University of Greifswald and DESY contributed to the work.

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