Battling COVID-19 with robots and a library of chemicals

Behind every good idea for a drug to fight COVID-19, there’s often a good library of chemicals.

At Yale, that library is at the Yale Center for Molecular Discovery (YCMD) — home to collections of 300,000 small molecules and 18,000 genomic probes. Researchers are already using these collections to look for existing drugs that could be repurposed to treat people with the novel coronavirus.

“Obviously, many Yale investigators are trying to understand the biology of the virus and develop therapeutic approaches to treat COVID-19,” said Yulia Surovtseva, the center’s director. “YCMD has the infrastructure, robotics, compound libraries, and technical expertise for high-throughput screening to rapidly test hundreds of thousands of drug-like molecules, including known drugs, for biological activity against coronavirus.”

High-throughput screening, used frequently in drug discovery, is often a starting point for identifying therapeutic candidates to treat illness and disease. Individual screening approaches called “assays” are tailored to ideas that researchers want to explore.

For example, YCMD can help researchers who are looking for existing drugs that kill a particular cancer cell, inhibit an enzyme that becomes hyper-activated during fibrosis, or disrupt two proteins that allow a virus to enter a human cell.

Each year, researchers from more than 40 Yale departments work with staff at YCMD, led by Surovtseva and executive director Craig Crews, Yale’s John C. Malone Professor of Molecular, Cellular, and Developmental Biology. The center currently has two staff members on site at Yale’s West Campus and three staff members working remotely, due to public health concerns amid the pandemic.

There are generally two screening approaches for drug discovery to treat a specific illness or disease, Surovtseva said.

One approach is to screen large collections of synthetic, little-known compounds that have drug-like properties. If a good chemical candidate emerges, the researcher will devise experiments to potentially optimize a new drug therapy.

Alternatively, a researcher can search for an existing compound from a collection, such as the library of 640 drugs already approved by the Food and Drug Administration to treat other diseases. Compounds from these collections may have a quicker route to clinical testing because much of their safety and toxicology profiling has already been completed for other uses.

Two Yale researchers are using the latter approach in their COVID-19 work with YCMD — with experiments from additional Yale laboratories on the way.

Dr. Craig Wilen, assistant professor of lab medicine and of immunobiology, has an assay with YCMD for screening COVID-19 and other coronaviruses against a collection of FDA-approved drugs. The goal is to prevent the virus from infecting human cells.

“We’ve made great progress and already found several existing drugs that inhibit viral entry of multiple coronaviruses,” Surovtseva said. “It is still a work in progress and we are repeating the screens and actively validating the results.”

YCMD also is working with assistant professor of neuroscience Junjie Guo. The Guo lab has developed new viral reagents that YCMD is using in a high-throughput microscopy assay to find known drugs that affect viral protein production. Testing of approved drugs is under way.

For these and other COVID-19 assays, part of the challenge is in converting an academic experiment into a “industry-style” experiment that investigates many compounds at once. Among the sophisticated instruments used for this are robotic liquid handlers that dispense tiny, five-nanoliter drops — about 10,000 times smaller than a raindrop — into palm-sized microplates that conduct 384 tests at a time.

The human element of the work is just as remarkable at this particular moment in history, Surovtseva said: “We are living in a time of real uncertainty, but our mission of service to society remains crystal clear. This work is of tremendous value and we feel honored to support it.”