Older chemical libraries show promise for fighting resistant strains of COVID-19 virus

SARS‑CoV‑2, the virus that causes COVID-19, continues to mutate, with some newer strains becoming less responsive to current antiviral treatments like Paxlovid. Now, University of California San Diego scientists and an international team of researchers have identified several promising molecules that could lead to new medications capable of combating these resistant variants.

Instead of looking for antiviral candidates from scratch, the research team screened 141 previously synthesized compounds that had originally been designed between 1997 and 2012 to inhibit a key enzyme called cruzain. Cruzain allows the parasite that causes Chagas disease to thrive in human cells. If left untreated, Chagas disease can lead to heart failure, organ damage, and even death.

The SARS-CoV-2 virus also depends on an enzyme, called M^pro, to replicate in host cells. Because cruzain and M^pro are structurally similar, the researchers reasoned that one or more of the anti-cruzain compounds might block SARS-CoV-2, too.

Five of the 141 molecules stood out for their ability to strongly inhibit M^pro. Two of these, dubbed compounds 1a and 5a, were particularly potent against M^pro. But because these compounds had been stored for over a decade, the researchers synthesized them in the lab to confirm their potency. They also synthesized a mirror-image version of 5a called 5b, because such molecules can often prove more powerful than the original version.

Laboratory testing of 5b demonstrated the strongest inhibition of M^pro, even at extremely low concentrations. 5a and 5b were also effective against the enzymes that allow SARS‑CoV and MERS‑CoV—two viruses closely related to SARS‑CoV‑2—to replicate. Both versions exhibited very high selectivity for the viral enzymes without significantly affecting human enzymes involved in normal cell function, an important consideration when developing drugs with fewer side effects.

In addition, advanced computer simulations revealed that compounds 5a and 5b bind to M^pro firmly enough to stop it from working, but not permanently, a property associated with potent yet safer drugs. The molecules demonstrated low toxicity in mammalian cells, reinforcing their potential as early‑stage drug candidates for further study, according to senior author Conor Caffrey, Ph.D., director of the Center for Discovery and Innovation in Parasitic Diseases at UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences.

The findings highlight the value of revisiting older chemical libraries to accelerate the development of next‑generation drugs at a time when the world continues to face evolving coronavirus threats and the potential for future pandemics.

The study is published in the Journal of Enzyme Inhibition and Medicinal Chemistry, and Caffrey is a co-inventor on a patent related to the technology described in this study.