1. Eynav Kliger 2016

2. Pharmaceutical R&D process  The average time of drug development - 13.9 years  The average probability of success in the cardiovascular system - 4.86%  Drug repositioning 2 Introduction

3. PAD – Peripheral arterial disease  PAD results from Atherosclerosis  Plaque built-up inside the arteries, blocks the blood flow in the peripheral arteries 3 Introduction

4. Atherosclerosis 4 Monocytes EC PMNLs Inflammation Endothelial dysfunction Anti- Inflammatory therapeutics Pro-angiogenic and Introduction

5.  MCP-1 – Monocyte Chemoattractant Protein-1  Involved in multiple sclerosis, atherosclerosis, allergy and asthma, diabetic retinopathy, lupus nephritis, cancer  Regulate leukocyte migration  Negative regulation of angiogenesis 5 Pro – angiogenic target CCL2 as an example Glucos-amino-glycan Introduction

6.  Chemokine (C-C motif) receptor 5  Expressed on T cells, macrophages, dendritic cells, eosinophils and microglia  Potential biomarkers in pulmonary arterial hypertension  Crucial for leukocyte recruitment  Positive regulation of inflammatory response 6 Anti – inflammatory target CCR5 as an example Introduction

7.  Therapeutics:  Pro-angiogenic targets  Anti-inflammatory targets  To find protein-protein interaction of PAD with known drugs  FDA approved drugs 7 Objectives Prediction of therapeutics Objectives

8. 8 89 pro- inflammatory targets 39 anti- angiogenic targets Literature review PINPAD protein-protein interaction of PAD 1233 proteins and 5726 interactions 3490 proteins and 21,164 interactions FDA-approved drugs from DrugBank 29 drugs5 drugs Mechanism of Action and original use of the drugs Literature review Methods

9. 9

10. 10 Results Literature review Anti- angiogenic pro- inflammatory Results

11. 11 Results PINPAD + FDA approved Anti- angiogenic pro- inflammatory Results

12.  Support for the potential biomarkers  No link to anti-angiogenic properties  Anti-angiogenic targets in PAD is a novel concept 12 Results Pro – angiogenic target CCL2 as an example Results

13. 13 Results Anti – inflammatory target CCR5 as an example Study case – Maraviroc targeting CCR5 Results

14. 14 Results Anti – inflammatory target CCR5 as an example Results

15.  Comprehensive predictions of potential drugs and drug targets for PAD patients  Collection of FDA- approved drugs targeting protein interaction found by network PADPIN  These predictions form a basis for further validation and future translational research in PAD 15 Conclusions

16. 16 Acknowledgement The paper authors 1 Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, USA 2 Division of Cardiovascular Medicine, Department of Medicine and Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, USA

17. 17 Thank you!

18. 18 Thank you! Personal interest MCP-1 Primed PMNLs Endothelial dysfunction Monocyte Pre-transmigration activation Monocyte differentiation Monocyte transmigration Monocyte differentiation Monocyte Post- transmigration activation CX3CR1 CD54 (ICAM) CD14 CCR2 MCP-1 CX3CR1 CD54 CD14 CCR2