UC Irvine scientists get ‘first shot’ in drug development to treat COVID-19

When the coronavirus pandemic hit, nearly everyone at the University of California, Irvine – and colleges across the country – had to abandon campus. But James nowick, professor of chemistry, was not part of this exodus. That’s because his lab, which designs and builds chemical molecules, had the right equipment to help the global push to find cures for COVID-19.

Nowick’s team got to work in April, and now on the bioRxiv preprint server, they describe the development of a ring-shaped molecule called a macrocycle which is designed to erase the machinery of the virus by blocking the action of an enzyme essential for its reproduction.

Adam Kreutzer, a project scientist in Nowick’s group, led efforts to design and produce the new molecule. “We weren’t sure for sure if we could synthesize the macrocycle, because sometimes macrocycles can be difficult to synthesize,” Nowick said.

But Kreutzer was successful on his first try with the macrocycle the team thought could work. “It’s a new molecule that has never been made before,” he said.

The researchers then tested the macrocycle to see if it could block the action of the coronavirus enzyme. The macrocycle binds to an enzyme molecule called the main protease which is necessary for the virus to function. The protease cleaves long chains of proteins that the virus forces its host cell to turn into separate components, which the virus then uses to continue to replicate.

The new macrocycle, Kreutzer said, “sits there in the active site of the enzyme and renders it non-functional.”

The research goes hand in hand with the lab work of Rachel Martin, also a chemistry professor at UC Irvine, which is determining the range of forms that the main protease of the coronavirus can take. The identification of these different structures is what allowed Nowick’s laboratory to design a macrocycle capable of locking onto the coronavirus.

This strategy for stopping the protease, Nowick noted, is the same as that used in a key class of drugs for the treatment of human immunodeficiency virus. But because viruses are so different, the same inhibitors cannot be used for both.

Nowick and his team named the University of California macrocycle, Irvine Coronavirus Inhibitor-1, or UCI-1, to indicate that this is the first molecule in what will still be a long journey to create a drug to treat or prevent COVID-19.

Now that Nowick’s lab has a prototype called an “initial hit,” researchers need to make additional molecules that are more effective at blocking protease. Then they have to figure out how to deliver the best molecule to the infected cells.

This means that while the new macrocycle is a promising first step, Nowick said, “people need to understand that this is far from a drug candidate.”

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