2013 Archived Content

Sixth Annual

Protein-Protein Interactions

Targeting PPI for Therapeutic Interventions

April 17-18, 2013

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THURSDAY, APRIL 18

7:45 am Breakfast Workshop Presentation (Sponsorship Opportunity Available) or Morning Coffee

8:15 Chairperson’s Opening Remarks

James Bibb, M.D., Associate Professor, Psychiatry and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center


Tomi K. Sawyer» 8:20 FEATURED PRESENTATION

Protein-Protein Interaction Drug Space: Stapled Peptide Drug Development

Tomi K. Sawyer, Ph.D., CSO, Aileron Therapeutics

Protein-protein interaction (PPI) drug space has become recognized as a promising new opportunity to advance a new modality of therapeutics for numerous diseases. The preponderance of such PPIs involve alpha-helical intermolecular recognition. This presentation will highlight recent advances in stapled peptide drug development.


Rational Design 

9:00 pH-Dependent Regulation of Cytokine-Receptor Interactions

Michael Hodsdon, M.D., Ph.D., Associate Professor, Laboratory Medicine, Yale University

Recognition of prolactin, a protein hormone and cytokine, by its receptor demonstrates a dramatic dependence on solution acidity across a physiologic range, such that acidification from pH 7.5 to 6.0 results in an approximately 500-fold decrease in affinity. This phenomenon has important implications for intracellular trafficking of endocytosed cytokine-receptor complexes. Biophysically, the pH-dependent behavior depends on a highly cooperative set of four histidine residues within the receptor-binding interface. A survey of cytokine-receptor complex tertiary structures reveals similar histidine-rich interfaces, which would be predicted to display similar pH dependence, along with histidine-free interfaces, expected to be pH independent. Site-directed mutagenesis can be used to rationally engineer pH-dependent behavior to both experimentally investigate its physiologic importance and also to potentially manipulate receptor trafficking.

9:30 Selective Protein-Protein Interactions Inhibition Result in Protection from Cardiac Ischemia and Reperfusion Injury

Nir QvitNir Qvit, Ph.D., Research Associate, Chemical and Systems Biology, Stanford University

We rationally identified a peptide inhibitor of one of several functions mediated by delta-PKC. Our inhibitor is an allosteric inhibitor of the kinase and therefore, unlike inhibitors of the catalytic site, unlikely to affect other kinases. This peptide is an inhibitor of protein-protein interaction, thus a member of a novel family of pharmacological agents with therapeutic promise.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing


Strategies to Regulate PPIs 

10:45 What Compounds for what PPI Target?

Olivier Sperandio, Ph.D., Drug Designer - CDithem Platform, Senior Research Associate, Inserm

I will describe our new iPPI-DB database that contains more than 1600 inhibitors of protein-protein interactions (iPPI) on about 15 classes of PPI targets with information on pharmacological activities, physico-chemical properties for the compounds, and biological descriptions about the PPI targets. The database was used to get some insight into the chemical space of iPPI with the ultimate aim of selecting PPI-friendly compounds to modulate PPI targets.

11:15 2P2I3D: A Focused Chemical Library Dedicated to Protein-Protein Interactions

Xavier Morelli, Ph.D., Group Leader & Principal Investigator, CRCM, CNRS

This talk will address some challenging questions: biological and chemical spaces of PPI with known orthosteric inhibitors, druggability assessment of protein-protein interactions, design and validation of chemical libraries dedicated to PPI.

11:45 Sponsored Presentation (Opportunity Available) 

 

Selcia12:15 pm Affinity Capillary Electrophoresis: An ACE method for Monitoring Protein-Protein Interactions (PPIs) 

Carol Austin, Ph.D., Biology Group Leader, Selcia Ltd

Affinity Capillary Electrophoresis (ACE) is a high resolution, separation technique capable of readily detecting PPIs in solution. The technique does not require either protein to be immobilised and protein consumption is in the pM-nM range. Inhibitors from a range of starting points can be detected from fragments to natural product extracts.

12:30 Walk and Talk Luncheon in the Exhibit Hall (Last Chance for Poster and Exhibit Viewing)

1:55 Chairperson’s Remarks

Cheryl Arrowsmith, Ph.D., Professor, Medical Biophysics; Canada Research Chair in Structural Proteomics, University of Toronto

2:00 Promiscuous Small-Molecule Protein-Protein Interaction Inhibition: Could This Be a Real Concern?

Peter BuchwaldPeter Buchwald, Ph.D., Director, Drug Discovery, Diabetes Research Institute, University of Miami

During our search for costimulatory interaction inhibitors, we have found poly-iodinated xanthene compounds that seem to be nonspecific promiscuous inhibitors of a number of PPIs within the tumor necrosis factor superfamily (e.g., (TNF-R– TNFalaf, CD40–CD154, RANK–RANKL, OX40–OX40L) as well as outside of it. For example, erythrosine B, and FDA-approved food colorant, acts as such an inhibitor with a remarkably consistent median inhibitory concentration (IC50) in the low micro-molar range. (approximately 2–20 mg/L) range.

2:30 Convergence of Mechanisms of Neuronal Injury and Cancer

James Bibb, M.D., Associate Professor, Psychiatry and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center

Cdk5 is now being found in sparse poplulations of cells outside the nervous system. For example, we have found it in neuroendocrine C cells of the thyroid. Furthermore, it is highly expressed in medullary thyroid carcinoma (MTC), a cancer that is derived from these cells. Inhibition of Cdk5 arrests human sporadic and familial forms of MTC suggesting Cdk5 can cause MTC tumorigenesis. We have generated an inducible/arrestible mouse model of MTC and have derived a target library of downstream effectors of CDKs. We have validated one downstream effect as the Retinoblastoma protein. We are now working to screen this target library with the goal of identifying novel oncogenic and neuronal injury mechanisms that can serve as the basis for drug development.  We will review these and our latest findings in this presentation.

3:00 Multiplex Analysis of Physiologic PPI Networks to Enable Identification of Signaling Signatures and Pharmacologic Targets

Adam G. SchrumAdam G. Schrum, Ph.D., Assistant Professor of Immunology, Mayo Clinic College of Medicine

Physiologic signal transduction is thought to be mediated by sets of PPI that can operate together in modular networks. We present a novel multiplex microspherebased approach to analyze network PPI profiles for the T cell antigen receptor (TCR) signaling pathway. The unique signatures emerging in response to functionally distinct stimuli provide a new  erspective on how to approach pharmacologic targeting of this immunologically important pathway.

3:30 Antagonism of Chromatin Interacting Proteins with Drug-Like Small Molecules

Cheryl Arrowsmith, Ph.D., Professor, Medical Biophysics; Canada Research Chair in Structural Proteomics, University of Toronto

4:00 End of Conference



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