X-ray screening identifies compounds blocking major coronavirus enzyme

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

“We tested 500 substances from the Karachi Natural Compounds Library if they bind to the papain-like protease of the new coronavirus, which is one of the main targets of an antiviral drug,” explains the lead author of the study, Vasundara Srinivasan of 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 an enzyme vital for the replication of the virus: when a cell is hijacked by the coronavirus, it is forced to produce design blocks for new virus particles. These proteins are made in the form of a long chain. PLpro 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, PLpro has another vital function for the virus,” says Srinivasan. “It blocks an immune system protein, called ISG11, which significantly weakens the cell’s self-defense. By inhibiting PLpro, we can also enhance the immune response of the cell.”

For the experiments, PLpro was mixed with each of 500 natural substances in a solution, giving them the opportunity to bind to the enzyme. It is not possible to see if a substance binds to the enzyme with a conventional light microscope. Instead, tiny crystals were grown from the mixtures. When illuminated by the bright X-rays of PETRA III at the P11 experimental station, the crystals produce a characteristic diffraction pattern from which the construction 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 material binds to it,” says Meents.

The screening showed that three phenols bind to the enzyme: hydroxyethylphenol (YRL), isolated for the experiments from the Lawsonia alba henna tree, is a compound present in many foods such as red wine and oil of virgin olive and used as an anti-arrhythmic agent. Hydroxybenzaldehyde (HBA) is a known anti-tumor agent and accelerates wound healing. It was isolated from the copper-leaved Acalypha torta. Methyl dihydroxybenzoate (HE9), isolated from French marigold Tagetes patula, is an antioxidant with anti-inflammatory effect and is found in green tea.

In subsequent laboratory tests , established and carried out by Hévila Brognaro in the group of Betzel, the three phenols reduced the activity of PLpro from 50 to 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: Superior Imaging of Matter. “These compounds are naturally present in many foods. However, drinking green tea will not cure your corona infection! Like it won’t heal your wounds or heal your cancer. Whether and how a corona drug can be developed from these phenols is under further study.”

In a different screening, a team made up of largely the same scientists had already screened thousands of existing drugs at PETRA III as possible inhibitors of the main coronavirus protease (Mpro) , also a pair of molecular scissors and a prime potential drug target. The screening identified several corona drug candidates, and the most promising entered 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-11”, Betzel points out.

In the new study, scientists from the University of Hamburg, the University of Sao Paulo in Brazil, Diamond Mild Supply in the UK, the European XFEL, the Bahauddin Zakariya University in Pakistan, the Israelita Albert Einstein Hospital in Brazil, the Pasteur Science Platform in Brazil, the European Molecular Biology Laboratory in Hamburg, the Fraunhofer Institute for Translational Medicine and of 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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