New Inhibitors of HIV latency reactivation

ABSTRACTCompany - Ithax Pharmaceutical is a new spin-off biotechnology company, located in Seattle, focused on developing proprietary small molecule chemistry to target RNA. The experience of its founders spans virology, drug design and RNA structure and function, and gives it a unique technological expertise in the RNA-targeting space. Their commercial expertise includes the successful founding, and subsequent sale, of Ribotargets, an RNA-focused small molecule drug discovery company in Cambridge, England in 1997-2001. This Phase I STTR proposal lays out a series of experiments, beyond the scope of academic discovery, that are critical to advance and de-risk the commercialization and pharmaceutical plans of the company. Successful completion of this project will help Ithax improve the efficacy of exciting lead compounds, validate their activity in relevant primary cell model systems, and obtain ADME and PK/PD data. The resulting progress would facilitate its commercial growth by providing the data required to initiating the pre-clinical development of its lead small molecules under a subsequent phase II SBIR project, and the acquisition of the private capital required for IND-enabling studies that will follow.Technology – The existence of latent but replication competent viruses residing primarily in a very small population of resting memory CD4+ T cells limits the long term efficacy of anti-retroviral therapy because the virus inevitably rebounds once therapy is suspended. Escape from latency is driven by transcriptional reactivation of the HIV provirus, which requires stimulation of RNA Pol II processivity by the host P-TEFb kinase, which is recruited to the HIV TAR RNA through its interaction with the viral Tat protein, the only transcriptional activator encoded by the virus. It follows that inhibition of the Tat-TAR-P-TEFb complex would lead to suppression of viral reactivation and prevents the virus emergence from latency. This project furthers the development of a new class of small molecule inhibitors of Tat-TAR-P-TEFb discovered by the company’s founders that interact with TAR RNA and inhibit viral replication in cells. It will optimize the biochemical and cellular potency of the lead using structure-based drug design; assess the lead’s pharmacological properties in vitro and its in vivo pharmacokinetics and toxicity and evaluate its activity and mechanism of action in sophisticated cellular models of latency. Collection of these data will allow subsequent submission of a strong phase II SBIR project focused on pre-clinical investigations, and the parallel pursuit of private capital required for IND-enabling studies. 1NARRATIVEIthax Pharmaceuticals develops new small molecule pharmaceuticals that target viral and cellular RNAs. Through this project, the company pursues the optimization and pharmaceutical development of a lead small molecule inhibitor of HIV latency reactivation. Such a therapeutic agent would greatly extend current anti- retroviral therapy regimens because it would suppress the re-emergence of the HIV virus from the latent reservoirs from which the virus inevitably rebounds once therapy is suspended, a step that is not targeted by any of the existing anti-retroviral drugs. 1