Targeting RNA conformation for drug development
DESCRIPTION (provided by applicant): One of the challenges of research in infectious diseases is to find ways to use the increasing knowledge of the mechanisms underlying disease transformation and progression to develop novel therapeutic strategies for AIDS. Targeting specific RNA- protein interactions, such as Tat-TAR or Rev-RRE, which are involved in proliferation and survival of HIV-1 is a promising approach. Our preliminary results show the ability of novel ligands to stabilize TAR RNA, inhibit Tat-TARinteraction at nanomolar concentrations and inhibit HIV-1 in MT-2 cells. These preliminary results will now be built upon to develop a library of conjugates to target Tat-TAR interaction that bind with high affinity and specificity to TAR. Proposed studies will further help establish the efficacy of this approach. The work proposed here, a multidisciplinary effort encompassing organic synthesis, biophysical chemistry and HIV pathogenesis describes the development of small molecule mediated inhibition of Tat-TAR inhibitors as HIV-1 therapeutics. The success of the proposed work would be a significant addition to currently available protein- specific approaches in AIDS therapy and RNA targeting. We propose using a 31 nt TAR target sequences to design conjugates that can be employed to inhibit Tat-TAR interaction; opening possibilities for developing small molecule RNA targeted HIV-1 therapeutics. PUBLIC HEALTH RELEVANCE: Several decades of research on the RNA structure has shown it to be an establisheddrug target, well known as a receptor for small molecule antibiotics. Though the bacterial ribosome has been a well known receptor for antibiotics blocking protein synthesis since the discovery of streptomycin in the 1940s, new antibacterial and antiviralapproaches are urgently needed to combat drug resistance, which severely limits the effectiveness of current antibiotics. To investigate the advantage of small molecule-based specificity coupled with charge/shape complementarity, we have initiated a program in the development of a approaches using multimeric ligands (consisting of ligands with independent binding sites) that can be used to target a specific RNA. This proposal focuses on the development of small molecule aminosugars (neamine) conjugates asan example of this approach. A comprehensive approach to identifying essential drug targets in multiple pathogens can be combined with our complementary approach of developing small molecules that bind with high affinity in a specific fashion to previously known as well as rapidly identified, new RNA targets. The inhibition of the Tat/TAR interaction, which facilitates HIV RNA transcription subsequently arrests HIV replication. The central hypothesis of this application is that conjugation of two ligandswith an independent binding sites can be conjugated with an appropriate linker to provide a high affinity TAR specific ligand, capable of inhibiting the Tat/TAR interaction at nanomolar concentrations. Furthermore, the assay is applicable to RNA based drugdiscovery where two pharmacophores with independent binding sites can be combined to select a high affinity ligand. Ultimately, the discovery of a TAR binding ligand with improved affinity and specificity over currently available molecules will provide abetter understanding for the potential use of a novel target for implementation in the fight against HIV. NUBAD is well equipped to synthesize the molecules and carry out the biophysical assays for inhibition. Select compounds identified from the assay that inhibit tat-TAR interaction at nanomolar Kd will be tested for inhibition of HIV.
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