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Suryaprakash Sambhara, DVM, Ph.D
Chief, Immunology Section, Influenza Division, CDC, Atlanta, USA

Making sense of pathogen sensors of Innate Immunity: Utility of their ligands as antiviral agents and adjuvants for vaccines.

Currently used antiviral agents act by inhibiting viral entry, replication, or release of viral progeny.  However, recent emergence of drug-resistant viruses has become a major public health concern as it is limiting our ability to prevent and treat viral diseases.  Furthermore, very few antiviral agents with novel modes of action are currently in development.  It is well established that the innate immune system is the first line of defense against invading pathogens.  The recognition of diverse pathogen-associated molecular patterns (PAMPs) is accomplished by several classes of pattern recognition receptors (PRRs) and the ligand/receptor interactions trigger an effective innate antiviral response.  In the past several years, remarkable progress has been made towards understanding both the structural and functional nature of PAMPs and PRRs.  As a result of their indispensable role in virus infection, these ligands have become potential pharmacological agents against viral infections.  Since their pathways of action are evolutionarily conserved, the likelihood of viruses developing resistance to PRR activation is diminished.  I will discuss the recent developments investigating the potential utility of the ligands of innate immune receptors as antiviral agents and molecular adjuvants for vaccines.

Shigeki Miyamoto, Ph.D.
Professor, McArdle Laboratory for Cancer Research – UW Carbone Cancer Center
Department of Oncology, School of Medicine and Public Health
University of Wisconsin-Madison

“Inside-out” NF-κB signaling in cancer and other pathologies

The NF-κB/Rel family of transcription factors contributes to critical cellular processes, including immune, inflammatory and cell survival responses. As such, NF-κB is implicated in immunity-related diseases, as well as multiple types of human malignancies. Indeed, genetic alterations in the NF-κB signaling pathway are frequently observed in multiple human malignancies. NF-κB is normally kept inactive in the cytoplasm by inhibitor proteins. Extracellular ligands can induce the release of NF-κB from the inhibitors to allow its migration into the nucleus to regulate a variety of target genes.  NF-κB activation is also induced in response to multiple stress conditions, including those induced by DNA-damaging anticancer agents. Although precise mechanisms are still unclear, research from our group has revealed a unique nuclear-to-cytoplasmic signaling pathway. In collaboration with bioengineers, clinicians and pharmaceutical industry, our lab has developed new methods to analyze primary cancer patient samples and identified several compounds with different mechanisms that mitigate this cell survival pathway.  Further contributions from other labs have also revealed additional mechanisms and molecular players in this “inside-out” signaling pathway and expanded its role in other physiological and pathological processes, including B cell development, premature aging and therapy resistance of certain cancers. Our own new findings, along with these recent developments in the field, will be highlighted.

Rajasekhar Chekkara, Venkata Reddy Gorla and Sobha Rani Tenkayala

Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies on Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK 1 inhibitors

Polo-like kinase 1 (PLK1) is a significant enzyme with diverse biological actions in cell cycle progression, specifically mitosis. Suppression of PLK1 activity by small molecule inhibitors has been shown to inhibit cancer, being BI 2536 one of the most potent active inhibitor of PLK1 mechanism. Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies were carried out for a set of 54 compounds belonging to Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK1 inhibitors. A six-point pharmacophoremodel AAADDR, with three hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R) was developed by Phase module of Schrdinger suite Maestro 9. The generated pharmacophore model was used to derive a predictive atom-based 3D quantitative structure-activity relationship analysis (3D-QSAR) model for the training set (r2 = 0.88, SD = 0.21, F = 57.7, N = 44) and for test set (Q2 = 0.51, RMSE = 0.41, PearsonR = 0.79, N = 10). The original set of compounds were docked into the binding site of PLK1 using Glide and the active residues of the binding site were analyzed. The most active compound H18 interacted with active residues Leu 59, Cys133 (glide score = −10.07) and in comparison of BI 2536, which interacted with active residues Leu 59, Cys133 (glide score = −10.02). The 3D-QSAR model suggests that hydrophobic and electron-withdrawing groups are essential for PLK1 inhibitory activity. The docking results describes the hydrogen bond interactions with active residues of these compounds. These results which may support in the design and development of novel PLK1 inhibitors.

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