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Accelerating Pharmaceutical R&D for PAD: Novel Drug Target Discovery

Explore the drug development process for Peripheral Arterial Disease (PAD), revealing novel protein-protein interactions and FDA-approved drug targets. This study offers insights for future translational research in PAD treatments.

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Accelerating Pharmaceutical R&D for PAD: Novel Drug Target Discovery

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  1. Eynav Kliger 2016

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

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

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

  5. Pro – angiogenic targetCCL2 as an example Introduction • 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 Glucos-amino-glycan

  6. Anti – inflammatory targetCCR5 as an example Introduction • 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

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

  8. Literature review 39 anti-angiogenic targets 89 pro-inflammatory targets Methods PINPAD protein-protein interaction of PAD 1233 proteins and 5726 interactions 3490 proteins and 21,164 interactions 29 drugs 5 drugs FDA-approved drugs from DrugBank Literature review Mechanism of Action and original use of the drugs

  9. Methods Methods

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

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

  12. Pro – angiogenic targetCCL2 as an example Results Results • Support for the potential biomarkers • No link to anti-angiogenic properties • Anti-angiogenic targets in PAD is a novel concept

  13. Anti – inflammatory targetCCR5 as an example Results Results Study case – Maraviroc targeting CCR5

  14. Anti – inflammatory targetCCR5 as an example Results Results

  15. Conclusions • 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

  16. The paper authors Acknowledgement 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. Thank you! Thank you!

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

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