Innovative Inhibitors Show Promise Against Coronaviruses by Targeting Mac1 Protein

A groundbreaking study published in mBio has unveiled the potential of modified inhibitors to combat coronaviruses, specifically by targeting the Mac1 protein domain, also known as the 'macrodomain.' This protein is an essential component found in all coronaviruses, including SARS-CoV-2 and MERS-CoV, and plays a critical role in the virus's ability to cause disease. The research, led by Dr. Anthony Fehr, Associate Professor of Molecular Biosciences at the University of Kansas, emphasizes the importance of the Mac1 domain in viral replication and highlights the promising avenues for antiviral therapies aimed at future coronavirus outbreaks.

The study's findings indicate that the newly developed molecules bind effectively to the Mac1 protein, inhibiting replication in cell cultures derived from both mice and human lung tissue. Dr. Fehr noted, "The macrodomain is critical for the virus's ability to cause disease. We've known for a long time that this gene is really important for the virus. Several groups, including ours, have started efforts to develop antivirals against it. But until recently, there hadn't been any proven compounds that could target this gene and affect the virus, at least in cell culture."

The researchers initially identified a compound named '4B' that showed promise in fitting into the Mac1 binding pocket with a significantly lower IC50, indicating that less of the drug would be required to inhibit viral activity. However, when tested in antiviral assays, the compound did not exhibit the expected effectiveness. Dr. Fehr explained that the compound's structure likely hindered its ability to penetrate cellular membranes due to a notable acid group, which is typically repelled by the hydrophobic nature of cell membranes.

To overcome this barrier, the research team undertook modifications to enhance the compound's cell permeability. By converting the acid into an ester, they successfully demonstrated robust antiviral activity, marking a pivotal moment in the research process. Dr. Fehr stated, "Once we did that, we started to see robust antiviral activity. This was the 'aha!' moment. We were finally able to make the compound cell-permeable and functional in cell culture. That was a big step."

The collaborative nature of this research was underscored by Dr. Fehr, who credited several co-authors, including Dana Ferraris, a chemistry professor at McDaniel College, and Lari Lehtiö, a biochemistry professor at Oulu University in Finland, who contributed significantly to the study's outcomes.

While the study showcases promising results, Dr. Fehr cautioned that coronaviruses could develop resistance to the inhibitors. However, this resistance is accompanied by a 'fitness cost' for the virus, suggesting that future generations with enhanced resistance may be less viable. This phenomenon underscores the potential for developing effective antiviral therapies that could render coronaviruses less harmful.

The research team continues to refine the promising molecules, emphasizing the importance of mouse models to assess the inhibitors' efficacy and stability in a living organism. As Dr. Fehr concluded, "This program has been crucial in supporting multiple groups working on inhibitors for viruses, parasites, and bacteria. It provides core facilities and resources that enable robust assay development and compound testing. While drug development is a long process, KU is equipped to quickly and effectively begin the process of identifying novel antimicrobial compounds."

With ongoing efforts in drug discovery and a commitment to advancing infectious disease research, the University of Kansas aims to play a pivotal role in addressing potential future coronavirus outbreaks, solidifying its position at the forefront of antiviral innovation.

For further details, refer to the full study by Jessica J. Pfannenstiel et al, titled "Identification of a series of pyrrolo-pyrimidine-based SARS-CoV-2 Mac1 inhibitors that repress coronavirus replication," published in mBio in 2025. DOI: 10.1128/mbio.03865-24.