Each year, millions of people worldwide suffer from potentially fatal infectious diseases that often leave survivors facing a lifetime of related health problems. But what if drugs against such diseases already existed but nobody knew it?

Scientists at Calibr, a non-profit drug discovery division of Scripps Research, are now exploring that question using an extensive library they've built of nearly all existing small-molecule drugs shown to be appropriate for direct use in humans.

The Calibr scientists are using this collection, called ReFRAME, to identify existing drugs that show promise for treating major diseases. As a result of this ReFRAME initiative, two FDA-approved drugs are already being tested in clinical trials—one as a treatment for tuberculosis and another for the parasite Cryptosporidium spp., a major cause of severe diarrhea—within only a few short years of Calibr scientists discovering their utility.

Now, in another early success of the project and demonstration of its power to quickly find much needed novel therapies, the Calibr researchers used ReFRAME to identify two additional compounds that in preliminary testing appeared effective against Cryptosporidium spp. The results of the new Cryptosporidium study were reported this week in Proceedings of the National Academy of Sciences.

"ReFRAME takes the concept of accelerating impact on patients through repurposing existing drugs to a new level, offering great potential for finding much-needed therapies more quickly and cost-effectively," says Pete Schultz. "The drugs we have assembled in ReFRAME have already been shown safe in humans, making them an incredibly valuable resource for tackling areas of urgent unmet medical need, especially neglected tropical diseases."

Drug discovery community 

"ReFRAME was developed as a singular new resource for the global health drug discovery community and is the largest and most comprehensive repurposing collection available. In addition to consolidating compounds from multiple existing collections, we synthesized around 5,000 molecules that are not commercially available—from which we identified the two new hits against Cryptosporidium."

Repurposing drugs, however, is not as simple as it sounds. Prior to ReFRAME, information on existing drugs was spread across multiple databases. Similarly, there was no single, comprehensive source of samples of the actual drug compounds, so collecting thousands of compounds to test against any given disease was a significant logistical challenge.

In their new study, Calibr scientists used the institute's high-throughput screening facility to test all 12,000 compounds against Cryptosporidium, a one-celled parasite that travels to the small intestine and bores into the intestine wall causing severe diarrhea.

Drug against the pathogen 

Currently approved treatment options for Cryptosporidium infection are limited to only one drug, nitazoxanide, which has modest potency and is ineffective in patients with compromised immune systems. Repurposing existing drugs was particularly appealing, as little drug discovery research targeting the parasite has taken place due to a lack of commercial interest in developing drugs against the pathogen.

Drugs that killed Cryptosporidium in the chambers were then given to mice infected with the parasite, and two drugs, VB-201(CI-201) and ASP-7962, proved effective at treating the infections in the animals. The researchers were able to move from identifying the compounds to animal studies in about two months, a remarkably rapid advance from one phase of drug discovery research to another.

"These two compounds show promise for providing therapeutics for targeting the parasite and not just the symptoms," says Case McNamara, Ph.D., a principal investigator at Calibr and coauthor on the paper. "If they prove effective at treating this disease in humans, it could impact the lives of millions of people worldwide."