This renewal involves integrated synthetic, mechanistic, mode of action, computer modeling, biochemical, imaging and preclinical studies directed at the design, synthesis and advancement of fundamentally new leads and strategies for the treatment of cancer, HIV/AIDS and potentially other therapeutic indications. These studies focus on understanding the molecular basis for cellular signaling through protein kinase C (PKC) and related pathways relevant to cancer treatment and other indications;on the development of novel synthetic approaches to promising therapeutic leads, especially those that exhibit unique activity relevant to cancer;on the development of drug and probe transporters, including new linker methodology;and on a promising strategy for using transporters to overcome Pgp based cancer resistance. Section D.1 describes continuing studies on the synthesis and biological evaluation of gnidimacrin and its analogs, the former a potent anticancer lead with in vitro and in vivo activity and a novel mode of action putatively involving selective PKC ?-II regulation;at the elucidation of the structural basis for this novel activity and mode of action;and at the design of simplified and potentially clinically superior candidates. Section D.2 is directed at the synthesis of synaptolepis factor K7, kirkinine and related functional analogs - the former two being potent anti-leukemic leads;at elucidation of the structural basis for their activity;and at the design of simplified and more effective candidates for advancing research on and potential clinical use of these novel leads. Section D.3 is directed at the synthesis of prostratin and its functional analogs, the former an active constituent in a medicinal tea used by healers in Samoa and now in preclinical development for eradicating HIV/AIDS virus through latent virus activation, and at evaluation of the promising anticancer activity of the analogs, their role in PKC signaling, and their ability to purge the latent virus from HIV infected cells as a clinical approach to HIV eradication. Section D.4 is directed at the development of methodology for the synthesis of new releasable drug-transporter conjugates designed to evade cellular Pgp efflux pumps in drug-resistant cancer cell lines and release free drug upon cell entry, providing a potentially general strategy to overcome Pgp-based resistant cancer and more specifically an approach to treating resistant ovarian cancer. Section D.5 is directed at the development of novel oligomerization strategies for the synthesis of new molecular transporters for drug/probe delivery and evaluation of their performance in transfected cells and transgenic animals. Collectively, this program provides for the first synthetic access to several designed and natural compounds with unique activities, including promising therapeutic leads and two leads in preclinical development, one designed to overcome Pgp-based resistance in ovarian cancer and a second targeting HIV/AIDS latent virus and thus a potential adjuvant for virus eradication.
This project involves integrated synthetic, mechanistic, computer modeling, biochemical mode of action and preclinical studies directed at several promising anticancer leads including one that is also a clinical candidate for eradicating HIV/AIDS virus through latent virus activation, at the preclinical advancement of a novel strategy for overcoming resistant cancer, potentially applicable to ovarian cancer, and at the study of new drug delivery systems with potentially broad fundamental and clinical utility in cancer therapy and disease detection. The project seeks to advance our ability to synthesize molecules, at the same time to uncover new modes of action and strategies that are relevant to cancer therapy as well as other therapeutic indications, and to introduce new drug or probe delivery strategies for disease diagnosis and treatment. The project provides for the creation of fundamental knowledge of broad potential utility and at the same time new approaches and agents to address unmet clinical needs in cancer, HIV/AIDS and other diseases.
|McKinlay, Colin J; Benner, Nancy L; Haabeth, Ole A et al. (2018) Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters. Proc Natl Acad Sci U S A 115:E5859-E5866|
|Haabeth, Ole A W; Blake, Timothy R; McKinlay, Colin J et al. (2018) mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice. Proc Natl Acad Sci U S A 115:E9153-E9161|
|Khan, Tapan K; Wender, Paul A; Alkon, Daniel L (2018) Bryostatin and its synthetic analog, picolog rescue dermal fibroblasts from prolonged stress and contribute to survival and rejuvenation of human skin equivalents. J Cell Physiol 233:1523-1534|
|Marsden, Matthew D; Wu, Xiaomeng; Navab, Sara M et al. (2018) Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents. Virology 520:83-93|
|Ryckbosch, Steven M; Wender, Paul A; Pande, Vijay S (2017) Molecular dynamics simulations reveal ligand-controlled positioning of a peripheral protein complex in membranes. Nat Commun 8:6|
|McKinlay, Colin J; Vargas, Jessica R; Blake, Timothy R et al. (2017) Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. Proc Natl Acad Sci U S A 114:E448-E456|
|Benner, Nancy L; Zang, Xiaoyu; Buehler, Daniel C et al. (2017) Vault Nanoparticles: Chemical Modifications for Imaging and Enhanced Delivery. ACS Nano 11:872-881|
|Pavlovic, Igor; Thakor, Divyeshsinh T; Vargas, Jessica R et al. (2016) Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo. Nat Commun 7:10622|
|Hsu, Hsiao-Tieh; Trantow, Brian M; Waymouth, Robert M et al. (2016) Bioorthogonal Catalysis: A General Method To Evaluate Metal-Catalyzed Reactions in Real Time in Living Systems Using a Cellular Luciferase Reporter System. Bioconjug Chem 27:376-82|
|McKinlay, Colin J; Waymouth, Robert M; Wender, Paul A (2016) Cell-Penetrating, Guanidinium-Rich Oligophosphoesters: Effective and Versatile Molecular Transporters for Drug and Probe Delivery. J Am Chem Soc 138:3510-7|
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