Description:

Translational Science: Clinical Leads for HIV/AIDS Eradication, Treatment of Alzheimer's And Cancer Immunotherapy

Paul Wender, PhD
Bergstrom Professor of Chemistry
Stanford University

Abstract:

Our research seeks to create therapeutic function through synthesis-informed design, often inspired by natural products and directed at unsolved medical problems. This lecture will focus on the as yet unachieved goal of eradicating HIV/AIDS, first-in-kind strategies for treating Alzheimer’s disease and the use of our own cells to make agents that elicit an immune response to overcome cancer. These function-oriented synthesis studies (Accts. 2015) will be initially exemplified with the organocatalytic synthesis of a new and remarkably effective mRNA delivery system, CARTS, directed at therapeutic vaccinations, cancer immunotherapy, and gene editing.[1] Our studies on HIV/AIDS eradication will follow. AIDS is one of the most catastrophic pandemics to confront mankind with ~37 million individuals living with AIDS and ~35 million who have thus far died of the disease (UNAIDS 2016). While antiretroviral therapy (ART) slows disease progression, it is chronic, requires strict compliance, is costly, and is implicated in health problems attributed to long-term chemo-exposure. HIV eradication would address these problems. ART is not curative. It reduces the active virus load, but the active virus is resupplied by reservoir cells incorporating genomically encoded, replication competent provirus that persist in infected individuals. Efforts to eradicate HIV seek to eliminate these reservoir cells, the cause of recurrent infection. Prostratin and bryostatin, promising clinical candidates for reservoir clearance, activate reservoir cells through a protein kinase C (PKC) pathway, allowing for their elimination through cytopathic effects or immunotoxin clearance. We have developed supply-impacting syntheses of prostratin[2] and bryostatin[3]. We have also used these routes to make superior analogs.[4][5] This lecture will provide an overview of our efforts directed at this global medical problem, including synthesis studies, computer[6] and REDOR solid state NMR studies[7] on the structure of PKC and PKC modulatory ligands, the design and synthesis of new PKC modulators, their latency activating activities (Nature Chem. 2012; PNAS 2013) and the connection of this research to a novel strategy to treat neurological disorders, with the lead candidate now in Phase II clinical trials for the treatment of Alzheimer’s disease.