Over half of all current drugs are based on natural products, while the marine environment which harbors the greatest biodiversity represents a largely untapped resource. I am leading a multidisciplinary marine natural products program that integrates isolation, synthesis, pharmacology, mechanism of action and early development studies. Our chemical investigations of mainly marine cyanobacteria have yielded novel marine natural products that act on a range of therapeutically relevant targets. A requisite for their development into therapeutics is the detailed characterization of their mechanisms of action, along with solving the supply problem. An integrative platform of pharmacological, genomic and proteomic profiling assists us in understanding their activities on the cellular and molecular level. Total synthesis and medicinal chemistry campaigns for prioritized compounds allows us to improve selectivity profiles. Rigorous biological evaluation directs us to specific disease indications and enables us to perform more targeted preclinical studies. My lab is producing a pipeline of bioactive compounds that are at various developmental stages, including cancer, ocular diseases, CNS diseases, viral diseases, and tropical diseases. Incorporation of upstream genome mining, biosynthetic gene cluster identification, and heterologous expression led to an integrated “Genomes to Natural Products to Drugs” initiative.
For example, we discovered the potent microtubule-destabilizer dolastatin 10 from a marine cyanobacterium and elucidated the biosynthesis. Dolastatin 10 has provided the basis for several marketed anticancer drugs. Antibody-drug conjugates (ADCs) of the dolastatin 10 analogue MMAE have been FDA approved for Hodgkin’s lymphoma and anaplastic large cell lymphoma (brentuximab vedotin), B-cell lymphoma (polatuzumab vedotin), refractory bladder cancer (enfortumab vedotin), relapsed/refractory multiple myeloma (belantamab mafodotin), various breast, gastric and urothelial cancers (disitamab vedotin), and metastatic cervical cancer (tisotumab vedotin). Our team also discovered a new chemical scaffold from marine cyanobacteria, gatorbulin-1, that targets a new tubulin pharmacological site. We reported the entire spectrum of the discovered chemical and biological novelties, including the isolation, structure determination, chemical synthesis, mechanism of action, target identification, and binding mode elucidation at the atomic level. We discovered, synthesized and performed the in vitro and in vivo evaluation as well as preclinical developmental studies for largazole, one of the most potent class I histone deacetylase (HDAC) inhibitors. We discovered apratoxins and subsequently characterized the novel mechanism of action through genomic and proteomic approaches, revealing that this class of natural products inhibits cotranslational translocation in the secretory pathway. Medicinal chemistry efforts paved the way for the development of synthetic apratoxins for pancreatic and colon cancer, retinal angiogenic diseases, and as broad-spectrum antivirals. We also discovered, synthesized and tuned selectivity profiles of protease inhibitors, GPCR modulators, cytoskeletal and cell membrane targeting agents, as well as many other natural products with various functions. In general, our team puts significant biology behind all discoveries to enhance the value of the natural products and to enable the best chances for development. We discovered approximately 200 natural products belonging to over 50 chemical scaffolds and have started to identify biosynthetic gene clusters from metagenomes and translating them (or key building blocks) into chemicals to address supply issues through heterologous production or a hybrid synthetic biology/chemistry approach (e.g., apratoxins).
Key words: Drug discovery and development; chemical and synthetic biology; marine natural products; specialized metabolites of cyanobacteria; structure determination; synthesis and biosynthesis of natural products; microbial genomics; mechanisms of action; functional and chemical genomics; high-throughput screening, assay development