With COVID-19 spreading rapidly across the globe, there is need to expedite discovery of drugs that can arrest the disease and vaccines to prevent individuals from contracting it. In this line, to identify drug candidates, U.S.-based researchers have developed an assay that can measure the effectiveness of candidate molecules in disrupting the invasion of host cells by the virus. From a list of 3,384 candidates in a database, they shortlist 25 small molecules that can be tested further. The preprint on this work was posted in bioRxiv. The preprint has not been peer-reviewed.
Mode of infecting
When the SARS C0V-2 virus attacks the cells in human body, the first step in the interaction is the way it makes contact and connects. The spike protein receptor binding domain (RBD) of the virus binds to the angiotensin-converting enzyme2 (ACE-2) in the host cell. This initiates the invasion of the host cell by the virus. Knowing this also provides a target for drug developers.
If the interaction between the viral RBD and ACE-2 of the host can be disrupted, the host cell would be protected from infection. Major efforts are therefore being made to dentify molecules that can disrupt this interaction.
Disrupting the link
The researchers from National Centre for Advancing Translational Sciences (NCATS), which is part of the U.S. National Institutes of Health, have developed a method to determine how effectively a drug candidate can disrupt the RBD-ACE-2 interaction.
In this assay, the RBD and ACE-2 are tagged with beads that can transmit a signal to each other. “When they are exposed to the candidate molecule, it either disrupts the RBD-ACE-2 binding process or not. So, when ACE-2 and spike are interacting, the beads are also close and pass a signal. When a drug (or antibody) blocks binding, the signal is lost, and this is the basis for the assays,” explains Matthew Hall, Acting Director and Biology Group Lead, Early Translation Branch, NCATS, in an email to The Hindu.
Repurposing drugs that were either approved by the Food and Drug Administration (FDA) for use against other diseases, or those that were not yet approved but had been shown to be safe in clinical trials, is a way to speed up the process of drug discovery in the case of this pandemic.
Other such drugs that have been repurposed are remdesivir and hydroxychloroquine. With such a speeding up in mind, the group tested 3,384 candidates in this assay, and the study yielded 25 high-quality, small molecule hits.
“Many of the 25 hits are small molecules. These are longer-lived and easier to handle, which is an advantage,” says Ramakrishnan Ramaswamy from the Department of Chemistry at Indian Institute of Technology Delhi, who wasn’t involved in this study. Many of the 25 molecules identified have been used in other contexts.
Further steps
“We are now testing these molecules in cell-based assays. The initial study was about sharing an important new biology approach (the assay), and showing it is useful for supporting therapeutic development for this approach. The activity in later assays will be important and give us confidence to develop them further (or not!),” says Dr Hall.
