Project Summary/Abstract: This renewal involves integrated and interdependent synthetic, mechanistic, structural, biochemical mode of action, computer modeling, collaborative and preclinical studies directed at the design, synthesis, assay and advancement of fundamentally new and unique therapeutic leads and strategies directed at unsolved global human health problems: the eradication of HIV/AIDS, novel treatments for Alzheimer's disease and multiple sclerosis, and the use of small molecules to enhance antigen density in antigen-targeted CAR T/NK cell therapies and 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 HIV/AIDS, but with cost, compliance, resistance and chronic chemoexposure 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 activate reservoir cells for subsequent clearance by the immune system, antibodies or immunotoxins. PKC modulators are also leading candidates for treating Alzheimer's disease (in current clinical trial), for cancer immunotherapy (clinical trial proposed for 2021), for multiple sclerosis and for many other unmet therapeutic needs. The lead PKC modulator, bryostatin 1, has been entered into clinical trials for AIDS eradication and Alzheimer's disease and is expected to be used clinically in a CRADA conducted by NCI scientists to enhance antigen expression in antigen targeted CAR T cell therapies for children with acute lymphoblastic leukemia who fail cell therapy because of low antigen density. Enabled by our scalable (now GMP) synthesis of bryostatin which represents the sole major supply of clinical grade material and our computational and REDOR solid state NMR structural studies relevant to bryostatin binding to PKC, plans are presented for the design, synthesis and evaluation of uniquely accessible “close-in” bryostatin analogs, super simplified analogs and two new families of clinically relevant PKC modulators, collectively directed at the identification of more efficacious, better tolerated and more synthetically accessible clinical candidates. New candidates will be evaluated in a range of “in house” assays and in advanced assays conducted by a network of collaborators expert in the clinically targeted areas.