Developmental Research Projects

Developmental Research Projects (DRPs) are intended to expand the scope and range of current research and investigators involved in antiviral discovery, allowing for testing of novel ideas and development of new technologies.

Over the past two decades, the world has witnessed various deadly viral pandemics, including the ongoing crisis caused by SARS-CoV-2. While vaccines provide hope, challenges such as persistent reservoirs, emerging variants, and vaccine hesitancy necessitate additional therapeutic options. Bacterial-derived small molecules offer a promising avenue to combat viral pandemics. To tap into the vast potential of unexplored natural products, Dr Brady’s group has developed a unique approach that combines bioinformatics and total chemical synthesis to create synthetic-Bioinformatic Natural Products (synBNPs). He will use this pipeline to discover and optimize novel small molecules with activity against pandemic viruses. By exploring a greater fraction of bacterial biosynthetic diversity, his research aims to identify nature-derived antiviral compounds.

Project Leader: Sean Brady, Ph.D.
Institution: The Rockefeller University
Location: New York, NY

Yellow fever (YF), caused by the yellow fever virus (YFV), poses a significant threat to human health. Recent reemergence events in non-endemic and historically low-activity areas highlight the urgent need to address YFV as a serious infectious disease. Currently, vaccination campaigns with the live-attenuated YFV-17D vaccine are the primary defense against YF and future outbreaks. The objective of Dr Ploss’s project is to identify novel inhibitors of YFV that can also suppress other flaviviruses. Through technical advancements, including full-length and subgenomic YFV genomes for high-throughput screening, he aims to discover potential antiviral compounds. His research team will validate hits using genetically diverse YFV strains, investigate resistance mutations, and assess the inhibitors' activity against other related viruses. 

Project Leader: Alexander Ploss, Ph.D.
Institution: Princeton University
Location: Princeton, NJ 

As viruses evolve, acquiring mutations, some advantageous and others incidental, the emergence of drug resistance poses a significant challenge for antiviral treatments. By utilizing a yeast genome-editing technique called eukaryotic multiplex automated genome engineering (eMAGE), this project will focus on efficient reverse genetics of positive-strand RNA viruses, specifically targeting MAVDA-prioritized CoVs, flaviviruses, and alphaviruses. The aims of this program include developing stable cDNA vectors, establishing renewable libraries for testing against DAA compounds, and optimizing the eMAGE workflow for generating virus variants integrated with mammalian cell culture assays. This innovative approach will enhance understanding of complex viral phenotypes and support research and therapeutic endeavors.

Project Leader: Brett Lindenbach, Ph.D.
Institution: Yale University
Location: New Haven, CT

Coronaviruses (CoVs) are RNA viruses responsible for deadly zoonotic events, including the current COVID-19 pandemic caused by SARS-CoV-2. Nidoviruses, including CoVs, possess a conserved RNA-dependent RNA polymerase (RdRp) responsible for viral RNA synthesis. Dr Campbell’s recent structural studies have identified a crucial pocket in the NiRAN domain, an N-terminal region of nidoviral RdRps, which plays a vital role in viral propagation and RNA capping. In this project, Dr Campbell aims to conduct a large-scale structure-based in silico docking screen targeting the NiRAN GTP/GDP binding site to identify potential drug or chemical leads. Validated hits will undergo further biochemical and structural characterization. This approach holds promise for the development of early therapeutics or chemical probes against CoVs.

Project Leader: Elizabeth Campbell, Ph.D.
Institution: The Rockefeller University
Location: New York, NY

Mentored Research Projects

Mentored Research Projects (MRPs) are intended to increase the availability of qualified researchers and other personnel for antiviral discovery research by providing opportunities to further their professional advancement. MRPs must relate to the Center objectives and may be used to support post-doctoral fellows, early career investigators, or senior investigators new to the field of antiviral discovery and development.

MRP Project: Targeting the SARS-CoV-2 RdRp for antiviral discovery efforts

Coronaviruses (CoV) have caused major zoonotic events, including SARS and MERS, and the ongoing Covid-19 pandemic. The high mutation rate of SARS-CoV-2 threatens current treatments. The RNA-dependent RNA polymerase (RdRp) protein, specifically the nsp12 subunit, is crucial for viral replication and an attractive target for antiviral therapies. However, nsp12 purification has been challenging, hindering drug target identification. This project aims to optimize nsp12 purification using established techniques, enabling the production of active holo-RdRp for inhibitor screening. A plate-based assay for transcriptional activity is being developed for high-throughput screening. Validated hits will undergo biochemical and structural analyses. This study aligns with MAVDA's objectives and aims to lay the foundation for SARS-CoV-2 drug development, benefiting future coronavirus outbreaks.

Project Leader: Wamiah Chowdhury, Ph.D.
Institution: The Rockefeller University
Location: New York, NY

MRP Project: Development of inhibitors against Chikungunya NSP2 protease

Chikungunya fever, caused by the Chikungunya virus (CHIKV), has become a global arboviral concern with no approved vaccination or antiviral treatment available. The CHIKV nsP2 protease, crucial for viral replication, presents an attractive therapeutic target. This project aims to purify the CHIKV nsP2 protease and establish a high throughput screening assay to identify potential drug molecules. Antiviral activity will be evaluated using in vitro and in vivo models. Molecular interactions between the protein target and drug candidates will be studied using techniques such as surface plasmon resonance (SPR), microscale thermophoresis (MST), and X-ray crystallography. The MAVDA mentored research program will provide valuable training in structure-activity relationship studies and expertise in structure-guided drug discovery, establishing a foundation for a career in drug development.

Project Leader: Subodh Samrat, Ph.D.
Institution: University of Arizona
Location: Tucson, AZ

MRP Project: Rapid high-throughput identification of SARS-COV2 drug resistance

The global impact of the COVID-19 pandemic, with 650 million cases and 6.5 million deaths, underscores the need for effective therapeutics. While monoclonal antibodies and small molecules have shown promise, the emergence of drug resistance poses a significant challenge. Several SARS-CoV-2 strains exhibit complete resistance to authorized monoclonal antibodies, raising concerns. In contrast, limited studies have explored resistance to small molecules, with only a few resistance-conferring mutations identified. To address this gap, we aim to investigate mechanisms of SARS-CoV-2 resistance to small molecule inhibitors, focusing on 3CL protease inhibitors like nirmatrelvir and ensitrelvir. Traditional resistance profiling methods are costly and time-consuming, hindering comprehensive studies. Therefore, we propose two innovative approaches utilizing attenuated viral strains to rapidly and systematically identify drug resistance, enabling informed next-generation drug design.

Project Leader: Sho Iketani, Ph.D.
Institution: Columbia University
Location: New York, NY