Application of marine natural products: Global health drug discovery, lead optimization, assay development, and identification of latent HIV reactivating agents.

摘要

Natural products have a longstanding history as clinical therapeutics, making them a valuable source of biomedically-relevant research tools. This dissertation describes the application of natural products as tools for drug discovery. By covering four different research projects, this thesis will cover a renovated approach to the classical utilization of marine natural products as screening compounds for primary hit identification, and semi-synthesis for lead development. Chapter 1 gives an overview of the current success and future challenges of natural products, with emphasis on marine-derived natural products. This chapter also includes a set of current literature examples that focus on identifying natural products with target selectivity in mind. The second chapter discusses the application of marine natural products in the discovery of antimalarials. This chapter includes the discovery and structure elucidation of the salinipostin A, a novel antimalarial chemotype with a bicyclic phosphotriester. The chapter ends with the secondary assays that were attempted to identify the mechanism of action of salinipostin A. The third chapter describes the development of the endoperoxide merulin A for the treatment of human African trypanosomiasis. The chapter closes with site localization studies of a merulin A-derived fluorophore in order to give insight into the mechanism of action of endoperoxides against T. brucei. Chapter 4 reports the development of a modular high-content high-throughput P. aeruginosa biofilm inhibition/dispersion screen. Assay development includes the assessment of the innate antibiotic tolerance from preformed biofilms. The results from a large scale screening campaign of a marine natural product library yield the identification of a new biofilm inhibitor skyllamycin B. The chapter ends with the evaluation of skyllamycin B and azithromycin as a co-dosing agent to eradicate preformed biofilms. The final chapter concentrates on the identification of abyssomicin II as a latent HIV reactivating agent. This is the first example of a bacterially-derived natural product to possess latent HIV reactivating activity. While potency excludes abyssomicin II from being a lead compound, mechanistic studies reveal that abyssomicin II reactivates latent HIV through protein kinase C and histone de-acetylase independent manner. These data suggest that the mechanism of latent HIV reactivation is novel.