This renewal involves integrated and interdependent synthetic, mechanistic, structural, biochemical mode of action, computer modeling, collaborative and preclinical studies directed at the design, synthesis and advancement of fundamentally new and unique therapeutic leads and strategies directed at unsolved global human health problems: the eradication of HIV/AIDS, the treatment of Alzheimer's disease, and small molecule enhanced cancer immunotherapy. HIV is one of the most catastrophic pandemics to confront mankind. Current antiretroviral therapy (ART) addresses the active virus, allowing one to live with AIDS, but with cost, compliance, resistance and chronic chemo exposure challenges. ART is not curative. Reservoir cells incorporating genomically encoded provirus episodically resupply the active virus. Elimination of these reservoir cells if done with ART is thus one of the most promising strategies to eradicate HIV/AIDS. Modulation of protein kinase C (PKC) represents one of the best strategies to eliminate reservoir cells. PKC modulators are also implicated in cancer (in clinical trials), Alzheimer's disease (in clinical trials), and many other unmet therapeutic needs. The lead PKC modulator, bryostatin 1, is now in the clinic for AIDS eradication, Alzheimer's disease and cancer. It supply is nearly, if not, exhausted. A plan is provided to address the supply problem through the scalable synthesis of bryostatin 1. At the same time, plans are proposed to use combined experimental (REDOR and DNP solid state NMR) and computational approaches to produce the first structural and dynamic analysis of PKC-bryostatin analog complexes in a membrane environment. This first-of-its-kind integrated synthesis/solid state NMR/computational approach will allow us to understand at a molecular level the binding of current PKC modulators to the PKC regulatory domain. That information will then inform the design of new PKC modulators. Our current bryostatin analogs (bryologs) are superior to bryostatin in all studies conducted thus far including binding, cell, animal and ex viv studies on primary cells from patients. Our newest bryologs exhibit unprecedented PKC selectivities. These and new analogs will be advanced through a comprehensive series of assays conducted by us and our collaborators. The resulting bryologs represent preclinical leads proving thus far to be superior to bryostatin and because of their simplified structure are significantly more synthetically accessible than bryostatin.
This project involves interconnected synthetic, mechanistic, structural, computer modeling, biochemical mode of action, preclinical, and collaborative studies directed at bryostatin 1, a compound now in clinic trials for the treatment of cancer and for two first-of-their-kind indications: the eradication of HIV/AIDS and the treatment of Alzheimer's disease. The supply of GMP bryostatin 1 is nearly if not exhausted, the future supply is at best uncertain, and it is likely that superior and more synthetically accessible agents could be identified. Plans to address these problems are presented including a) a strategy for the scalable synthesis of bryostatin 1, b) a first-of-its-kind integrated experimental and computational plan to understand at a structural and dynamic level how bryostatin binds to its protein kinase C (PKC) targets in a membrane environment, and c) the use of that knowledge to design, synthesize and preclinically advance potentially superior and more synthetically accessible analogs for the eradication of HIV/AIDS, treatment of Alzheimer's disease and small molecule enhanced immunotherapy.
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