New bioactive HIV antiviral compounds

by S. C.

Trana Discovery and Southern Research Institute announced that several bioactive hits from a set of 15,000 diverse small molecule compounds screened under contract with the NIAID exhibit antiviral activity against HIV-1 infected cells.

Among the compounds tested at Southern Research using the Trana HIV 201 High-Throughput Screening (HTS) assay, 16 compounds demonstrated inhibition of HIV replication in infected human cells and several of these compounds were judged to be “potentially druggable.”

The screening assay used to identify the compounds is based on the premise that HIV-1 has evolved to use tRNALys3 as a primer for initiation of reverse transcription. Therefore, the interaction between tRNALys3 and viral genomic RNA represents a potential novel target for HIV-1 drug development. The biochemical assay to identify inhibitors of the interaction between tRNALys3 and HIV-1 genomic RNA was developed by Trana and transferred to Southern Research for high-throughput screening. Southern Research converted the assay to a homogeneous amplified luminescent proximity assay using AlphaScreen® reagents from PerkinElmer.

During this initial pilot study, 164 compounds were identified from the diversity set library as hits. Of these hits, 136 were retested in dose-response against HIV-1IIIB replication in a CEM-SS cytoprotection assay. Sixteen of this last group of compounds inhibited HIV-1 replication.

"These data indicate that the Trana Discovery assay has identified a number of compounds with modest antiviral activity against HIV-1," said Roger Ptak, Co-Principal Investigator, Southern Research Institute, in his report to the Division of Acquired Immunodeficiency Syndrome (DAIDS) within NIAID. "Additional testing of compounds with similar structures, as well as broader HTS, should lead to the identification of lead compounds that inhibit HIV-1 replication through the novel mechanism of inhibiting the interaction between tRNALys3 and viral genomic RNA."