Viral polymerases are reliable targets for controlling infections caused by many pathogens. Active site inhibitors of these polymerases, i.e., nucleoside analogs, have proven to be very effective at suppressing viral replication when used in combination with drugs that target other viral proteins. A good example of the utility of viral polymerase inhibitors is emtricitabine, which is a component in seven different FDA approved combination therapies. The interaction between the CXCR4 receptor and its endogenous ligand, CXCL12, synchronizes many essential physiological (homeostatic regulation of leukocyte trafficking, hematopoiesis, embryonic development, etc.) and pathophysiological (overexpression in &gt;20 tumor types, induction of CXCR4-mediated transcription of growth/angiogenic factors, upregulation of immunosuppressive cytokines, etc.) roles. In principle, CXCR4 antagonists can modulate these pathophysiological morbidities either when used directly as anti-cancer monotherapies or in combination with immuno-oncologic agents. Especially active targets in this area have included hematopoietic stem cell mobilization and chemosensitization. In addition, since the CXCR4 receptor serves as one of the host co-receptors responsible for mediating HIV-1 entry into immune cells, compounds that block entry could potentially be used as HIV therapeutics. My lab has discovered a series of CXCR4 modulators that, depending on their binding orientations, can act as either potent antagonists or inverse agonists of CXCR4 cell surface receptors. In addition, we have discovered a series of dual tropic antagonists with excellent safety profiles that simultaneously block HIV entry through both CXCR4 and CCR5. In this presentation, I will discuss some of the opportunities and challenges associated with the development of each of these series. Finally, I will also describe a chemoinformatics/machine learning protocol, called FRESH, that dramatically increases the ease of quality candidate identification. To date, novel compounds, identified by FRESH and subsequently synthesized, were consistently found to have nanomolar or sub-nanomolar activity for several dissimilar proteins. These results strongly suggest that artificial intelligence will have great utility in the design of biologically active molecules.

Award Address (Alfred Burger Award in Medicinal Chemistry sponsored by Gilead Science Inc.). Discovery and development of novel therapeutics for treating viral diseases, cancers, and inflammatory disorders

255th National Meeting (2018)

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