Technology

The Ribonucleoprotein (RNP) Complex

At AGS, our drug discovery platform focuses on an under-explored drug target, the ribonucleoprotein (RNP) complex. Targeting RNPs is challenging due to the multiple roles, dynamic conformations, and chemical instability of these complexes. To address this challenge, we have developed a robust cell-based screening platform dedicated to targeting these complexes.

Targeting Ribonucleoproteins (RNP) Complexes
Advantages:

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.

Platforms
High Throughput Screening (HTS) Assay 

In viruses, RNPs are integral components of many regulatory systems including transcription, nuclear export, stability, localization, and translation. There is an increasing appreciation that RNPs are suitable drug targets. This stems in part from the fact that RNA can adopt complex tertiary structures, with binding pockets for ligands or proteins that structurally resemble those found in enzyme active sites and at protein-protein interfaces. While the chemical character of RNA binding sites may be somewhat different from those of proteins, often involving highly charged surfaces, interactions can occur with very high affinities and specificities. 

We have developed a proprietary cell-based High Throughput Screening platform specifically designed to target Ribonucleoproteins (RNPs). Cell-based assays provide the most realistic environment for the presentation of the RNP. These assays have the additional advantage of presenting multiple steps of the RNA pathway, any one of which may potentially be inhibited. In contrast, in vitro assays present only a snapshot of an RNP in a single conformation and may fail to capture the most "druggable" target state. Cell-based assays also filter out many compounds with poor solubility, uptake, localization, or toxicity.