Targeting RNA to Beat Drug-Resistant Strains

Dr. Paul Agris is a biochemist, but he sees himself as a quality control engineer for cellular activity. When mutant cells spur the growth of a tumor, or bacteria or viruses replicate and produce an infection, defective molecular products result. Issuing a massive “recall” to eliminate the defective products is often too difficult to succeed, Agris says. So, he suggests shutting down the cellular factories that are churning them out and fixing the machinery inside to stop the process altogether.

The equipment in need of repair in Agris’ scenario is the ribonucleic acid (RNA) in cancer cells, bacteria, and viruses. He has studied the molecule for four decades and says its ability to regulate protein synthesis makes it a prime target for disease intervention. “We don’t need to knock out huge quantities of proteins,” he says, noting many drugs are designed to bind to and disrupt specific proteins. “We can just go after a small bit of RNA in each cell to shut down the ability to express a protein.”

Targeting RNA is both simpler and more complex than going after a protein, Agris says. While proteins have 20 possible chemical building blocks, RNA has only four. That makes it harder to design a drug specific to RNA based solely on unique chemical properties, he says. Instead, researchers need to study the structure of the 3-D polymer, including the way it folds over on itself and how enzymes modify certain segments so potential targets can be identified. “You need to do a lot more upfront investigation to ensure the target is so distinct you don’t have any peripheral effects,” he says. On the other hand, once the target has been achieved, he says, RNA’s limited arsenal of chemistries makes it nearly impossible for the molecule to modify itself and become drug-resistant.

“We have a huge problem globally with antibiotic resistance but few new antibiotics.”

Drug resistance is a primary focus for Agris, who last year spun out his technology, including assays and reagents to test for candidate drugs, to a new company called Sirga Advanced Biopharma. The company recently won a National Institutes of Health grant to develop its process, and Agris wants to begin by studying HIV and a variety of bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Almost one-third of people with HIV develop resistance to one of more of the components in the drug cocktail designed to keep the virus in check, he says, and MRSA has become a major cause of infections in hospitals. “We have a huge problem globally with antibiotic resistance, but few new antibiotics are produced against innovative targets because there’s little profit in making them,” he says. “Finding a drug that is effective against these diseases is critical, and that is my goal.”

 

Dr. Paul Agris says RNA is a logical target for disease intervention because it controls the protein synthesis necessary for bacteria, viruses, and cancer cells to replicate. In the illustration below, his technology would disrupt the transfer RNA molecule (multicolored) before it could decode the genetic information of the bronze-colored protein and synthesize a new protein.