Fast Track Proposals will be accepted. Direct to Phase II will not be accepted. Number of anticipated awards: 1-2 Budget (total costs): Phase I: $300,000 for up to one year; Phase II: $2,000,000 for up to 3 years. Background Therapeutic targeting of RNA may be a strategy which could inhibit the translation of one or more disease-associated proteins. Antisense technologies have been highly effective; however, these technologies rely on derivatized oligonucleotide structures which have poor cell permeability and biodistribution which limits their effectiveness as a therapeutic. The identification of detailed RNA structures now allows the design of small molecules which are capable of binding to RNA with high selectivity and specificity. This strategy has the potential to expand the use of small molecules beyond inhibiting functional activity, by preventing the translation of mRNAs, so that the targeted protein is never expressed. Small molecule drugs have been developed that successfully inhibit several HIV intracellular proteins. However, a number of HIV proteins have not been successfully inhibited since they lack a reactive site that can bind a small molecule. By developing small molecules to selectively bind to key sites on transcribed HIV RNA the translation of RNA to protein may be inhibited for any HIV intracellular protein. Targeting one or more HIV RNA sequences with small molecules may be an effective way of shutting down viral replication, preventing cellular transmission and ultimately leading to sustained viral remission. Project Goal The goal of this SBIR solicitation is to support the discovery and design of RNA-targeted small molecules which specifically bind to HIV RNA transcripts to prevent RNA processing and translation into protein. Phase I activities may include, but are not limited to: • Designing, optimizing and testing strategies for the targeting of small molecules to key sites on HIV RNA. • Performing proof-of-concept studies to demonstrate that small molecule binding to HIV RNA can prevent processing and translation into proteins in relevant cell lines and primary cells. • Evaluating off-target effects. • Performing proof-of-concept studies in an HIV animal model. Phase II activities may include, but are not limited to: • Optimizing delivery to target HIV infected cells with minimal off-target effects. • Evaluating organ toxicity, immune responses/adverse events and pharmacokinetic/pharmacodynamic parameters in nonhuman primates. • Performing IND-enabling studies in consultation with the FDA.