Researchers at the University of California San Diego, along with an international team, have found several promising molecules that may lead to new treatments for COVID-19 variants that are less responsive to existing drugs such as Paxlovid.
Instead of starting from scratch, the scientists examined 141 compounds previously developed between 1997 and 2012. These compounds were initially designed to target cruzain, an enzyme critical for the survival of the parasite responsible for Chagas disease. This disease can cause severe health problems if left untreated.
The research team noted that both cruzain and Mpro—the main enzyme used by SARS-CoV-2 to replicate—share structural similarities. This led them to hypothesize that some anti-cruzain compounds might also inhibit SARS-CoV-2.
Out of the screened molecules, five showed strong inhibition against Mpro. Two in particular, named compounds 1a and 5a, demonstrated significant potency. Due to their age, these compounds were resynthesized in the laboratory to verify their effectiveness. A mirror-image version of 5a, called 5b, was also synthesized because such versions sometimes show greater biological activity.
Laboratory tests indicated that compound 5b was especially effective at inhibiting Mpro even at low concentrations. Both forms (5a and 5b) also worked against enzymes essential for replication in related viruses SARS-CoV and MERS-CoV. Importantly, these compounds targeted viral enzymes without substantially affecting human cellular enzymes—a factor important for minimizing side effects.
Further computer modeling suggested that both versions bind tightly but not permanently to Mpro—a feature often associated with potent but safer medications. Tests showed low toxicity in mammalian cells according to 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.
“These 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,” said Caffrey.
The full study is available in the Journal of Enzyme Inhibition and Medicinal Chemistry.
