Proteases as Drug Targets: Technologies and Opportunities for Drug Discovery

TABLE OF CONTENTS

Chapter 1 Executive Summary

Chapter 2 Introduction To The Proteases

Overview of Proteases

• Catalytic Function
• Categories of Proteolysis
• Proteases, Proteinases, and Peptidases
• EC Classification of Proteases
• Serine Endopeptidases
• Cysteine Endopeptidases
• Aspartic Endopeptidases
• Metalloendopeptidases
• Threonine Endopeptidases

Overview of Protease Inhibitors

• Low-Molecular Weight Inhibitors
• Natural (Protein) Protease Inhibitors

Regulation of Proteolysis

• Proteolytic Cascades
• Proteases as Signaling Molecules
• Compartmentalization of Proteolysis

Chapter 3 Strategies For Protease Inhibitor Discovery

Overview of Therapeutic Protease Inhibitors

Discovery of Small Molecule Protease Inhibitors

• Proteomics-Based Approaches
• Role of High-Throughput Screening
• Trends in Lead Optimization
• Integrated Use of Technologies

Mechanisms of Protease Inhibition

• Competitive Reversible Inhibitors
• Competitive Irreversible Inhibitors
• Allosteric Inhibitors
• Inspiration from Nature

Determination of 3D Protease Structures

• X-ray Crystal Diffraction
• Solution NMR
• Homology Modeling.

Structure-Driven Drug Discovery

• Use of Structures to Generate Leads
• Fragment-Based Methods
• Recent Successes in the Protease Field

Identifying Protease Substrates

Chapter 4 Protease Inhibitors In Infectious Disease

Introduction

HIV/AIDS

• Overview of HIV Protease Inhibitors
• First-Generation Peptidomimetic Inhibitors
  • Limitations
• Improved Peptidomimetic Inhibitors
• Non-Peptidomimetic Inhibitors
• Strategies to Enhance Inhibition
• Shape of Protease Inhibitors to Come

HCV

• Overview of HCV Protease Inhibitors
• HCV Protease Inhibitors In Development.

Rhinovirus

SARS Coronavirus

Bacteria

Candida

Plasmodium and Other Parasites

Chapter 5 Protease Inhibitors In Inflammatory Disorders

Inflammation and Tissue Injury

• Osteo- and Rheumatoid Arthritis
• Chronic Obstructive Pulmonary Disease
• Miscellaneous

Protease Targets

• Serine Endopeptidases
  • HNE
  • Kallikrein
  • Trypsins and Tryptases
• Cysteine Endopeptidases
  • Cathepsin S
  • ICE
  • Caspases
• Metalloendopeptidases
  • Matrix Metalloproteinases
  • ADAM and ADAM-TS Families
  • Procollagen C-proteinase
• Proteasomes
• Miscellaneous

Chapter 6 Protease Inhibitors In Cancer

Overview of Cancer

• Established Therapies
• Molecular Targeted Therapies

Proteolytic Cascades in Cancer

• Matrix Remodeling Cascades
• Fibrinolysis Cascade
• Apoptosis Cascades
• Cell Cycle Cascade

Protease Targets

• Serine Endopeptidases
  • uPA
  • Transmembrane Proteases
• Cysteine Endopeptidases
  • Caspases
  • Cathepsin B
• Metalloendopeptidases
  • Broad-Spectrum Inhibitors
  • Next-generation MMP Inhibitors
  • ADAMs Family
• Proteasomes
• Exploiting Tumor Proteases

Chapter 7 Protease Drugs In Other Conditions

Introduction

Cardiovascular Diseases (Main Focus)

• Background
• Protease Targets for Inhibition
  • ACE in Cardiovascular Diseases
  • ACE in Miscellaneous Diseases
  • ACE2
  • Renin
  • ACE/NEP, NEP/ECE

Anticoagulation

• Background
• Protease Targets for Inhibition
  • Thrombin
  • Factor Xa
  • FactorXa/Thrombin
  • Factor VIIa

Thrombolysis

• Background
• Thrombolytic Proteases

Neurodegenerative Diseases

• Background
  • Secretases in Alzheimers Disease
• Protease Targets for Inhibition
  • ƒÁ-Secretase
  • ƒÀ-secretase
  • Caspases
  • Miscellaneous

Osteoporosis

• Background
• Cathepsin K Inhibitors

Type 2 Diabetes

• Background
• DPP-IV Inhibitors

Acute Diarrhea

• Background
• Encephalinase Inhibitors

Chapter 8 Market Considerations and Forecasts

• Introduction
• Infectious Disease
• Inflammation/Tissue Injury
• Cancer
• Cardiovascular Conditions
• Neurodegenerative Diseases
• Other Conditions
• National Market Forecasts

Chapter 9 Company Profiles

• Abbott Laboratories
• Amedis Pharmaceuticals Ltd
• AngioDesign Inc
• Arriva Pharmaceuticals Inc
• Astex Technology
• Bayer AG
• Biopharmacopae Design International Inc
• Boehringer-Ingelheim GmbH
• Celera Genomics
• Cellzome
• Collagenex Pharmaceuticals Inc
• Curacyte AG
• De Novo Pharmaceuticals Ltd
• Dendreon
• Gilead Sciences Inc
• GlaxoSmithKline plc
• Incyte Corporation
• Locus Technology Inc
• Medivir
• Millennium Pharmaceuticals Inc
• Myriad Genetics Inc
• NeoGenesis Pharmaceuticals
• Nereus Pharmaceuticals Inc
• Novartis Pharma AG
• Ono Pharmaceuticals Co. Ltd
• SIGA Technologies Inc
• Syrrx Inc
• Torii Pharmaceutical Co. Ltd.
• Vertex Pharmaceuticals
• Wilex AG

Chapter 10 Trends and Opportunities

• Building on Successes
• Learning from Clinical Failures
• Exopeptidases as Drug Targets
• Serine Endopeptidases as Drug Targets
• Cysteine Endopeptidases as Drug Targets
• Aspartic Endopeptidases as Drug Targets
• Metalloendopeptidases as Drug Targets
• Threonine Endopeptidases as Drug Targets
• Prospects in Acute Diseases
  • Infectious Diseases
  • Acute Inflammatory Diseases
• Prospects in Chronic Diseases
  • Inflammation/Tissue Injury
  • Cancer
  • Cardiovascular Diseases
  • Other Diseases
• Exploring Allosteric Inhibitors
• Exploring Irreversible Inhibitors
• Challenges for Future PI Discovery
• Toward Systems Biology Approaches

Chapter 11 Glossary

TABLE OF EXHIBITS

• Exhibit 2.1 Important Proteases.
• Exhibit 2.2 Overview of Protease Clans and Families
• Exhibit 2.3 EC Classification of Proteases
• Exhibit 2.4 Listing of Proteases by EC Classification
• Exhibit 2.5 Protease Inhibitors Used in Research
• Exhibit 2.6 Naturally Occurring Protease Inhibitors
• Exhibit 2.7 Protease Inhibitors In Commercial Development
• Exhibit 4.1 Protease inhibitors in Infectious Disease
• Exhibit 5.1 Protease Inhibitors in Inflammatory Conditions
• Exhibit 6.1 Protease Inhibitors in Cancer
• Exhibit 7.1 Protease Inhibitors in Miscellaneous Disorders
• Exhibit 8.1 Protease-related Markets by Indication
• Exhibit 8.2 World Pharma Market in 2003 and 2009
• Exhibit 8.3 World Protease-related Market in 2003 and 2009