Project: "Leveraging High-Throughput Microfluidic Technologies to Quantify Drug Resistance"
Q1. What is your project focused on?
- Inevitable drug resistance plagues antiviral drug development, limiting the lifetime of drugs that are costly to develop. The ability to predict resistance to inhibitors would be transformative, allowing for the prioritization of durable inhibitors over susceptible ones. The central premise of this proposal is that to combat eventual resistance, we need methods to proactively identify potential resistance mutations to lead inhibitors early in the drug development pipeline, which requires an understanding of how variation in viral protein sequence influences its function and inhibition (i.e., a drug resistance landscape). To generate this landscape, we adapt high-throughput microfluidic technologies to measure viral protein function and inhibition for libraries of thousands of viral protein mutants with lead inhibitors identified by QCRG. These microfluidic devices have thousands of small chambers (each less than a nanoliter in volume) that allow us to assay thousands of different viral protein variants and see how they respond to our lead inhibitors. Our goal is to identify lead inhibitors with few mutational avenues to resistance to prioritize for antiviral drug development (i.e., inhibitors that are resistant to resistance).
Q2. How does your project align with the Center’s objectives?
- The technology developed in this proposal has the potential to benefit all of the AViDD center’s projects, as it can be adapted to different targets. Our work will help the Center not only advance clinical candidates, but advance clinical candidates that have the potential to be the most durable in the clinic.
Q3. What is the most inspiring aspect about your project/research focus?
- The central goal of this project is to flip the script on antiviral drug development to focus on how variation in the protein target can lead to resistance to lead inhibitors. This would represent a significant shift in the current ligand-centric drug development paradigm and could potentially lead to the development of more effective antiviral drugs that are less vulnerable to resistance. Furthermore, this approach could save time and resources be enabling the prioritization of durable inhibitors early in the drug development pipeline.
Q4. Do you think collaboration is important for the progression of your research? If so, why are you interested in connecting with members of the QCRG?
- Absolutely. Our work will benefit immensely from the collective knowledge QCRG members have on specific antiviral targets. We anticipate benefitting from interactions with each of the QCRG projects and the Cores, and ultimately our methods could be integrated into the Screening Core.
Q5. What are your thoughts on the importance of building pandemic preparedness?
- The COVID-19 pandemic has shown us how devastating a viral outbreak can be on a global scale. Prospective development of durable antivirals to viruses of concern is one, of many, important ways we can invest in pandemic preparedness and help us fight future outbreaks.