薬剤標的としてのプロテアーゼ：創薬の技術と機会

Abstract

Proteases are a superfamily of enzymes with important roles in the regulation of cellular protein activity. There are at least 475 known and putative proteases and 103 homologs to known proteases in humans, and it is estimated that up to 1,200 human genes encode proteases. Successful established protease inhibitor drugs on the market act by inhibiting key proteases. Their success has led to proteases being increasingly viewed as valuable drug targets in disease treatment and a range of protease inhibitors are in various stages of commercial development.

Scope

This Report offers a comprehensive review of the global protease market. The Report discusses strategies to design peptidomimetic and non-peptidomimetic competitive inhibitors, as well as other types of inhibitors. The main disease areas where proteases or their inhibitors are involved include infectious diseases, inflammation and wounds, cancer, cardiovascular conditions, neurodegenerative diseases, and more are examined. In addition, this report profiles key companies active in the protease drug discovery area.

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
  • γ-Secretase
  • β-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