Translating Nature's Library: Future Opportunities through Function Oriented Design

Molecular evolution on Earth over the past 3.8 billion years has produced an extraordinary library of chemical structures, unsurpassed in number, diversity and function. Collectively these molecules comprise the chemical genome of our planet and represent a universe ripe for exploration. We have only just begun to explore this molecular world but the early lessons learned are revolutionizing the whole of science as all disciplines from anthropology to zoology are being “molecularized”. Much emphasis thus far has been justifiably placed on static structure although increasingly attention is turning to the “systems chemistry” and “systems biology” of our dynamic natural world. This lecture will expand upon these perspectives (Nature 2009, 197 – 201) with an emphasis on how we can use the lessons learned from Nature to achieve what Nature has not done well or not done at all as it “selects” for natural function rather than human needs. A special strategy toward this end is what we have dubbed “function oriented synthesis” (FOS: Accts 2008, 40 – 49) which uses bio-inspired, computation- and synthesis-informed design to achieve function, often superior to that found in Nature. This strategy has been used to design agents based on plant-derived prostratin (Science 2008, 649 – 652) that are superior to prostratin and now in preclinical development for the eradication of HIV/AIDS, an as yet unachieved but transformative goal. A second example is found in our decades long work on marine-derived bryostatin (lead ref: PNAS 2011, 6721 – 6726) which has led to designed functional analogs (bryologs) that are superior in function to the natural product in a variety of comparative in vitro, in vivo, and ex vivo assays and more readily supplied (Nature Chemistry 2012, 705 – 710). These leads are being advanced preclinically in collaboration with a new company focused on first-in-class approaches to cognitive dysfunction including Alzheimer's disease. A third example of FOS is found in our studies on agents that breach biological barriers (membranes, BBB, skin, ocular, etc). Through reverse engineering of the protein HIV Tat, we were the first to propose that its ability to enter cells is a function of the number and spatial array of its guanidinium groups (PNAS 2000, 13003 – 13008; Nature Medicine 2000, 1253 – 1257). This seminal translation of Nature's lead spawned the design and implementation of a wide range of superior “cell penetrating molecular transporters” (Drug Discovery Today: Technologies 2011, e49-e55) capable of ferrying small molecules, optical probes, peptide, proteins, plasmids, metals, siRNA (PNAS 2012, 13171 – 13176), vaults and quantum dots among others across cell and tissue barriers and even the cell walls of algae (PNAS 2012, 13225 – 13230). These transporters can be targeted in a manner that is complementary to monoclonal targeting (Bioconjugate Chem. 2006, 787 – 796). They have also been shown to overcome Pgp based resistance, a major cause of cancer chemotherapy failure and the basis for a new company directed at resistant disease (PNAS 2008, 12128 – 12133; Gynecologic Oncology 2012, 118 – 123).