Translational science comes to the fore

Protease inhibitors might help to manage COVID-19

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IRVINE, Calif.—A chemist at the University of California, Irvine (UCI), has made a COVID-19 drug discovery. Dr. James Nowick and his team have been working on a novel protease inhibitor called a macrocycle that essentially disables the COVID-19 virus protease, the part of the virus responsible for replication, and prevents infected patients from becoming sicker from increased viral load.
The successful application of protease inhibitors in COVID-19 is an example of translational science, innovative research and the spectrum of work going into long-term treatment possibilities to help control this pandemic and manage COVID-19. Drug discovery of protease inhibitors became important with HIV, as such inhibitors became one of the key reasons HIV-positive patients can live healthy lives without a vaccine.
Adam Kreutzer, a project scientist in Nowick’s group, spearheaded the effort to design and produce the new molecule. Nowick said they weren’t sure if they could synthesize their target, but Kreutzer succeeded on his first try with the macrocycle the team thought might work.
The UCI researchers tested the macrocycle to see if it could block the action of the coronavirus enzyme. The macrocycle binds to the main protease necessary for the virus to function. That protease cleaves long strings of proteins that the virus forces its host cell to make into separate components, which the virus then uses to keep replicating. The new macrocycle, according to Kreutzer, “sits there in the active site of the enzyme and makes it nonfunctional.”
The research is related to work in the lab of Dr. Rachel Martin, also a UCI professor of chemistry, who is determining the range of shapes that the coronavirus’s main protease can take. Identifying these various structures enabled Nowick’s lab to design a macrocycle that can lock onto the coronavirus. This strategy for stopping the protease, Nowick noted, is the same used in a key class of drugs for treating HIV, but because the viruses are so different, the same inhibitors cannot be used for both.
Nowick and his team named the macrocycle University of California, Irvine Coronavirus Inhibitor-1, or UCI-1, to indicate that it 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 in blocking the protease. Then they must figure out how to actually deliver the best molecule to infected cells. This means that while the new macrocycle is a promising first step, Nowick stated that, “People need to understand that it’s a long way from a drug candidate.”
“The identification of an initial hit is only a first step toward the identification of a drug candidate,” he continued. “We next need to improve the inhibitor to achieve stronger inhibition. We also need to test whether the molecule and improved analogues can enter infected cells and stop the virus. Further preclinical studies will then be necessary, including those involving animal models. Although we are excited about the results, we still have a long way to go.”
Nowick explained that the UCI-1 macrocycle was synthesized by Fmoc-based solid-phase peptide synthesis, followed by cyclization in solution phase, deprotection and purification by HPLC. He added, “UCI-1 is designed to bind to the active site of the SARS-CoV-2 main protease enzyme through non-covalent interactions. This approach is a different from a number of other inhibitors that have been reported, which rely on covalent bond formation to the active site cysteine of the protease.”
The next steps are to get an X-ray crystallographic structure that will further guide the structure-based drug design process and allow the design of inhibitors with improved activity and other properties, and to determine whether UCI-1 and improved analogues can enter cells and block the replication of the virus. “Once we have an analogue with good activity in cells, we will be ready to test the compounds in an animal model,” Nowick remarked.
“We believe that improved homologues will have commercial potential. For this reason, we have filed a provisional patent application that encompasses UCI-1 and its analogues,” he reported. “I could envision drugs that come from this work, as well as the efforts of others, leading to treatments for COVID-19. I could also envision prophylactic preventions, akin to PrEP as a prevention for HIV/AIDS. Had these efforts been done back in the SARS outbreak of 2003, or perhaps the MERS outbreak in 2012, we might have had a drug in hand to fight the current pandemic. There will likely be additional coronavirus pandemics in the future that will benefit from the current drug development efforts against COVID-19.”

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