Targeting Ribonucleoproteins (RNP) Complexes


Targeting the essential activities of RNP complexes has several advantages over traditional drug targeting strategies.

RNA in the context of an RNP is a structural component with features amenable to targeting by inhibitors (see below).

The activity of a viral RNP complex is frequently absent in the host cell, thus, a molecule that specifically targets the RNP has a low likelihood of cross-reacting with an endogenous complex. In many instances viral RNA and viral proteins form direct interactions, a scenario that is ideal for targeting with an inhibitor.

Viruses use their genomes economically and the same RNA sequences that make up a protein binding pocket can also encode for proteins. Thus, mutations that confer resistance to a small molecule inhibitor are less likely to arise because such changes can result in both structural changes to the RNA and amino acid substitutions in the protein and are more likely to reduce the fitness of the virus.

Viruses have evolved resistance to each class of currently marketed antiviral drugs. Thus, there is great need for new classes of antiviral therapeutics to combat resistance to older drugs.

Proof of Concept

The principle that RNP complexes represent good therapeutic targets has been demonstrated by the by development of the blockbuster drugs Zithromax, a macrolide antibiotic that targets the 50S subunit of the ribosome, and Zyvox, a oxadolidinone antibiotic that interferes with translational initiation. At AGS, our goal is to do for antivirals what this target class has already done for antibacterials.