Dr. Luis Montaner is an HIV expert focused on finding new ways to boost the natural function of the immune system to combat infection or viral-associated disease. Dr. Joseph Salvino is a medicinal chemist and an expert in drug discovery and identification of novel small molecule lead compounds. The two have combined their expertise to design a strategy to modulate the immune response to viral infections using novel small molecules. They discuss the basis of this approach and how they are advancing it.
Montaner: We are born programmed to resist viral infections. One of the key weapons our immune system uses to respond to viruses is interferon, which “interferes” with the viral replication. However, sometimes our system is not effective. Our goal is to amp up the natural immune response to COVID-19 in a targeted way without inducing greater inflammatory damage in the lung.
Salvino: Interferons activate the immune response by engaging a specific receptor present on the cell surface. We are developing compounds that stimulate binding of interferons to their receptor and activate signaling to the cell to initiate an antiviral response. We have some interesting lead compounds that we are testing to confirm they have the intended biological effect without toxicity.
Montaner: Joe and I have been collaborating for the past three years to find small molecules that can modulate immunity in HIV by acting on the interferon response, as one of my lab’s interests is what happens when this response becomes chronic and poses problems.
Salvino: For this project, we have now tested about 20-30 thousand compounds based on computer models and predictions. We were looking for inhibitory compounds that block the interaction of interferons with their receptor, but we have also come across stimulatory compounds that have the opposite effect and can actually serve as a glue between ligand and receptor.
Montaner: When the COVID-19 outbreak started, we realized we had those molecules in our hands that could potentially be helpful and limit the disease by amplifying the interferon antiviral response. These small molecules act as cement between interferon and receptor, making the interaction more stable and, as a consequence, strengthening the stimulation provided on the immune cell. We don’t want to make it irreversible, though. We want to maintain an off switch because the immune cells are not programmed to be on a constant inflammatory state and that could lead to tissue damage, for example to the lungs in the case of COVID-19.
So, we looked back at several molecules that in our studies made the interferon response better. The platform we developed to test our inhibitory compounds in vitro and in vivo gives us the advantage of time because we don’t need to set up new systems and assays; we already have them in place. Basically, we are steps ahead in the process because we already have candidate molecules and the appropriate tools to test them. We are evaluating these compounds to track their effect on the immune response in vivo.
Salvino: There are limited small molecule drugs available to fight viral infections and, in general, they work by directly interacting with the virus. For example, a compound could bind to the “Spike” of COVID-19 to block the virus from entering the host cells; or it could directly bind to an essential component in the virus to reduce its ability to function. However, viruses have the ability to mutate and become resistant to drugs, and that small molecule could lose effectiveness. Our approach is different because it targets the host and has a reduced likelihood of causing resistance compared to virus-directed approaches.
Montaner: These small molecule drugs can potentially amplify the natural antiviral response and prevent the COVID-19 virus from establishing an infection, or rapidly fight it off. In theory, such therapeutic booster could be used alone at onset of symptoms or later on in combination with other antiviral drugs.
Salvino: This work is very collaborative. Our labs complement each other, since my expertise in organic and synthetic chemistry is combined with Luis’s immunology and biology expertise.
Montaner: As a basic biomedical research institute, Wistar makes fundamental discoveries and generates proofs of concepts for potential new therapies. For example, after identifying new compounds, we study their activity and test them in preclinical models. Once these steps are complete, partnerships with industry become critical in order to translate our discoveries into new medicines.
We believe our work to identify small molecules to boost the immune response against viral infection could potentially be important in the COVID-19 crisis, and for other diseases, but even getting to the point at which a new candidate drug is attractive to industry partners requires extensive work and robust financial support.