This Phase I SBIR proposal is the initial step of a critical path initiative designed to develop and validate small molecule inhibitors of a novel drug target regulating platelet production in humans. The scope of work builds on strong genetic and biochemical evidence linking redox-dependent enzymatic activity of biliverdin IX reductase (BLVRB) in a previously-uncharacterized regulatory pathway of megakaryocyte development and enhanced platelet production. Preliminary data applying virtual computational modeling of the BLVRB crystal structure have identified ten compounds predicted to inhibit ligand binding and redox coupling, observations that will be iteratively refined in two synergistic aims designed to identify lead compounds retaining enzymatic inhibitory functions using stringent biochemical and confirmatory cell-based assays (target validation). Long- term success is predicated on synergistic expertise in platelet biochemistry and drug development that will logically extend into Phase II SBIR compound optimization and in vitro characterization. Successful completion of the research has fundamental relevance to commercial development of a new class of platelet- enhancing compounds functioning independently of the known thrombopoietin (TPO)/c-MPL receptor axis. Compound development and target validation using BLVRB redox inhibitors would represent a highly innovative strategy that would theoretically bypass associated toxicities associated with direct TPO/c-MPL agonists currently in clinical studies such as platelet activation, thromboembolic complications, and bone marrow fibrosis.
Human blood platelets stop bleeding, and low platelet counts cause life-threatening hemorrhage. Approaches to temporarily correct low platelet counts include platelet transfusions from donors (difficult to obtain and costly), and medications which are known to be associated with platelet activation, blood clotting, worsening platelet counts and bone marrow scarring. The approach taken in this early-stage Phase I SBIR application builds on development of a new class of compounds for a highly novel drug target identified in our laboratory that regulates platelet counts in humans. The applicant small business organization Blood Cell Technologies was specifically developed for early stage R&D focusing on commercial development of diagnostics and therapeutics important for human blood diseases. A drug development program targeting a distinct oxidation-reduction reaction represents an innovative platelet-enhancing strategy unrelated to previous drug targets. The scope of work builds on strong genetic evidence linking the enzymatic function to enhanced platelet counts in humans, identifies a novel pharmacologic target for development, and represents a new mechanism of action that may have broader implications for redox biology in hematopoiesis. Long-term success is predicated on synergistic expertise in platelet biochemistry and drug development that is anticipated to logically extend into Phase II SBIR compound optimization and in vitro testing upon characterization of initial compounds. Successful completion of the research has fundamental relevance to commercial development of a new class of compounds that enhance platelet counts in humans.
| Nesbitt, Natasha M; Zheng, Xiliang; Li, Zongdong et al. (2018) In silico and crystallographic studies identify key structural features of biliverdin IX? reductase inhibitors having nanomolar potency. J Biol Chem 293:5431-5446 |
| Chu, Wen-Ting; Nesbitt, Natasha M; Gnatenko, Dmitri V et al. (2017) Enzymatic Activity and Thermodynamic Stability of Biliverdin IX? Reductase Are Maintained by an Active Site Serine. Chemistry 23:1891-1900 |
| Wu, Song; Li, Zongdong; Gnatenko, Dmitri V et al. (2016) BLVRB redox mutation defines heme degradation in a metabolic pathway of enhanced thrombopoiesis in humans. Blood 128:699-709 |
