Human Applications

Human Applications

 

Trana Discovery provides a proprietary drug discovery technology platform that enables its partners to discover new treatments of bacterial and viral infectious diseases. Our assays screen compounds to identify potential drug candidates that work through a novel mechanism of action: inhibition of the target pathogen(s) ability to use an organism-specific transfer RNA (tRNA), essential for propagation.

 

 

The Role of tRNA

 

Scientists at Trana Discovery have long understood the crucial role of transfer RNA (tRNA). All organisms need tRNA for normal propagation. Inhibition of tRNA during RNA replication or blocking its recruitment during assembly should stop the replicative cycle, and the pathogen would not be able to survive. Founders of Trana Discovery helped characterize the structure of tRNA, particularly of the ultra-conserved region, the anti-codon stem loop (ASL), of this complex protein. If chemicals that bind to the ASL region could be identified, thereby inhibiting the action of tRNA, new drugs could be crafted for use in treating human and animal diseases.

Assays

Novel Technology

 

Trana Discovery technology exploits this conserved region of tRNA. As infectious organisms are selected as targets, a unique probe, based on a pre-determined sequence, is developed to mimic the chemical structures of the ASL. The probe is then employed in a high-throughput screening process to identify compounds that react with high affinity and inextricably bind to the ASL, indicating discovery of a molecule that possesses tRNA inhibitory activity specific to the target pathogen. By inhibiting the role of tRNA, propagation cannot proceed, thus stopping pathogen growth and spread of infection. Because each pathogen has a unique combination of tRNAs, compounds with highly selective anti-infective characteristics will target only the pathogen and in turn avoid disruption of normal flora, resistance issues, or superinfections.

 

 

 

 

 

 

Read our Paper

 

The Discovery and Characterization of Novel Bioactive Small Molecules Targeting the Priming Complex of HIV-1.

Staphylococcus aureus 201 HTS Assay

 

The Trana Staphylococcus aureus 201 High-Throughput (HTS Assay identifies compounds that inhibit the essential use of a S. aureus unique tRNAArg that is required for protein synthesis. The assay identifies compounds that interfere with the interaction of an oligonucleotide mimic of the ASL loop of tRNAArg with a programmed ribosome.The validated assay was used to screen a 60,000 compound library from which 283 compounds were initially identified. These compounds were retested in a dose response curve and 89 compounds were confirmed as biochemically active.

 

Thirty-eight of these compounds were selected based on an acceptable IC50 concentration and tested in a bacterial assay where eight compounds demonstrated activity against two or more strains of S. aureus. Strains tested included MRSA strains, vancomycin resistant strains and MDR strains.  The two most active hits were further characterized to establish a true antibiotic effect.

 

 

 

 

Further experiments with all eight bioactive hits demonstrated that six of the eight inhibited polypeptide synthesis directly.

 

The assay is now fully HTS functional and is immediately available for licensing to the pharmaceutical industry for the discovery, development, and market availability of critically needed new anti-infectives.

HIV 201 HTS Assay

 

The Trana HIV 201 High-Throughput (HTS) Assay – designed to identify compounds that inhibit the use of tRNA by HIV – has the ability to select compounds with anti-HIV bioactivity. Because tRNA is essential for HIV replication, disruption of the virus’ ability to use tRNA would represent a novel target for anti-HIV drug therapy.

 

 

Scientists at Trana Discovery have developed the patented technology that forms the basis for the assay used to screen molecular libraries for tRNA inhibitors. The technology centers on the anticodon stem loop (ASL) of tRNA and the importance of nucleotide modifications within the ASL. The ability to synthesize copies or mimics of the ASL with the modifications, just as they occur in nature, is what overcomes previous barriers to high-throughput screening and enables further research and the application of Trana Discovery technology to methodically search for compounds that inhibit interactions with tRNA.

 

 

 

 

 

 

The Trana HIV 201 High-Throughput (HTS) Assay – designed to identify compounds that inhibit the use of tRNA by HIV – has the ability to select compounds with anti-HIV bioactivity. Because tRNA is essential for HIV replication, disruption of the virus’ ability to use tRNA would represent a novel target for anti-HIV drug therapy.

Trana Discovery, Inc. | 2054-260 Kildaire Farm Road Cary, NC 27518 | info@tranadiscovery.com | (919) 295-6116