Pharmaceutical Biocatalysis: Fundamentals, Enzyme Inhibitors, and Enzymes in Health and Diseases

 

Description:

This book provides an overview of the world market of therapeutic enzymes and enzyme inhibitors, rare diseases, orphan drugs, the costs of drug development and therapies, and enzymes in downstream processing of pharmaceuticals. It discusses carbonic anhydrase inhibitors and their multiple drug interactions, carboxylesterase inhibitors for pharmaceutical applications, employment of inhibitors for the treatment of neurodegenerative diseases, use of engineered proteins, bioactive peptides, and fibrinolytic enzymes for thrombolytic therapy, and enzymes important for the design and development of new drugs/drug metabolites such as aldehyde oxidases and cytochrome P450 enzymes and the role the latter play in vascular biology and pathophysiology. The treatment of cancer is explored in connection with enzymatic amino acid deprivation therapies and new drugs that act as chemical degraders of oncogenic proteins. The book also introduces the resistance mechanisms of cancer. Furthermore, it provides an insight into the relationship between pathological conditions of cardiovascular disease and oxidative stress. The text also focuses on the potential use of nanoparticles as carriers for enzymes with medical relevance, computer-aided drug design for the identification of multi-target directed ligands, and the development of improved therapeutics through a glycan-“designer” approach. It concludes with an introduction to the chemoenzymatic synthesis of drugs.

 

Table of Contents:

 

1. Pharmaceuticals: Some General Aspects

1.1 Introduction

1.2 General Remarks

1.3 Orphan Drugs and Rare Diseases

1.4 The World Market of Pharmaceuticals, Therapeutic Enzymes, and Enzyme Inhibitors

1.5 Drug Development Process, Risks, and Costs of Drug Development, and Prescription Drug Prices

1.5.1 Drug Development in Europe and Germany

1.5.2 Risks in Drug Development and Mitigation Strategies

1.5.3 Randomized Clinical Trials and Beyond

1.5.4 Prescription Drug Prices

1.5.4.1 Cost reduction: public–private drug partnerships

1.6 Concluding Remarks

2. Use of Enzymes in the Downstream Processing of Biopharmaceuticals

2.1 Introduction

2.2 Cell Dissociation and Lysis

2.2.1 Cell Dissociation

2.2.2 Cell Lysis

2.3 Impurity Clearance

2.3.1 Nucleic Acid Clearance

2.3.2 Protein Clearance

2.4 Targeted Structural Modifications

2.4.1 Affinity Tag Removal

2.4.2 Precursor Maturation

2.4.3 Structural Modification of Impurities

2.4.4 Glycosylation

2.5 Discussion

2.5.1 Points to Consider

2.5.2 Pros and Cons

2.6 Conclusions

3. Therapeutic Use of Carbonic Anhydrase Inhibitors and Their Multiple Drug Interactions

3.1 Introduction

3.2 First- and Second-Generation Clinically Used Sulfonamides and Their Drug Interactions

3.3 Sulfonamides with Diuretic Action: Bumetanide, Hydrochlorothiazide, Furosemide, Indapamide, and Chlortalidone

3.4 Sulfonamides/Sulfamates as Antiepileptic Drugs: Sulthiame, Topiramate, and Zonisamide

3.5 Celecoxib, Valdecoxib, and Polmacoxib as CA/COX-2 Inhibitors

3.6 Inhibitors of Carbonic Anhydrases as Antitumor Agents

3.7 Conclusions and Repurposing Old Drugs for New Disease Approaches

4. Fibrinolytic Enzymes for Thrombolytic Therapy

4.1 Introduction

4.2 Status of Anticoagulants and Antiplatelets

4.2.1 Heparin and Derivatives

4.2.2 Coumarin Derivatives

4.2.3 Thrombin Inhibitors

4.2.4 Factor Xa Inhibitors

4.2.5 Antiplatelet Drugs

4.3 Thrombolytic Drugs

4.3.1 Plasminogen Activators as Thrombolytic Drugs

4.3.1.1 First-generation plasminogen activators as thrombolytic drugs

4.3.1.2 Second-generation plasminogen activators

4.3.1.3 Third-generation plasminogen activators (by protein engineering)

4.3.2 Direct-Acting Plasmin-Like Thrombolytic Drugs

4.3.2.1 Non-microbial thrombolytic enzymes

4.3.2.2 Microbial thrombolytic enzymes

4.4 Conclusion

5. Role of Engineered Proteins as Therapeutic Formulations

5.1 Introduction

5.2 Protein Engineering Approaches

5.2.1 Directed Evolution

5.2.1.1 Asexual methods

5.2.1.2 Sexual methods

5.2.2 Computational Designing

5.2.2.1 Rational designing

5.2.2.2 De novo designing

5.2.3 Combinatorial Approach

5.3 Protein Therapeutics

5.3.1 Antibodies

5.3.2 Enzymes as Therapeutics

5.3.3 Cytokines and Their Receptors

5.3.4 Hormones

5.3.5 G-Protein Coupled Receptor Targeting Antibodies

5.3.6 Cardiovascular Therapeutics

5.3.7 Coagulation Factors

5.4 Protein-Based Scaffolds for Therapeutic Applications

5.4.1 Monobodies

5.4.2 SH3 Domains/Fynomers

5.4.3 Lipocalins/Anticalins

5.4.4 Nanobodies/VHH Domains

5.4.5 DARPins

5.4.6 Affibodies

5.4.7 Avimers

5.4.8 Knottins and Cyclotides

5.4.9 Kringle Domain

5.4.10 Kunitz Domain

5.5 Concluding Remarks

6. Synthesis of Bioactive Peptides for Pharmaceutical Applications

6.1 Introduction

6.2 Synthesis of Bioactive Peptides

6.2.1 Chemical Synthesis

6.2.1.1 Synthesis in solution

6.2.1.2 Solid-phase peptide synthesis

6.2.1.3 Sequential condensation of solid phase fragments

6.2.2 Enzymatic Synthesis

6.2.2.1 Classification of proteolytic enzymes used for peptide synthesis

6.2.3 rDNA Technology

6.2.3.1 Fusion expression

6.2.3.2 Direct expression

6.2.4 Other Novel Peptide Synthesis Methods

6.2.4.1 Utilizing microwave energy for peptide production

6.2.4.2 Ligation

6.2.4.3 Recent developments

6.3 Purification, Characterization, and Nanoformulation of Biopeptides

6.3.1 Purification

6.3.1.1 High-performance liquid chromatography for biopeptide purification

6.3.1.2 Capillary electrophoresis

6.3.1.3 Affinity chromatography

6.3.2 Characterization Methods

6.3.3 Nanoformulation

6.4 Pharmaceutical Application of Bioactive Peptides

6.4.1 Antimicrobial Agent

6.4.2 Anticancer Agent

6.4.3 Antihypertensive Agent

6.4.4 Bioactive Peptides for Skin Disease Treatments

6.4.4.1 Skin infections and biofilms

6.4.4.2 Skin cancer and hyper-pigmentation

6.4.4.3 Skin burns

6.4.4.4 Diabetic foot ulcers and other chronic skin wounds

6.4.5 Bioactive Peptides as Immuno and Cytomodulatory Agents

6.4.6 Other Novel Pharmaceutical Applications

6.5 Conclusion

7. Cardiovascular Disease and Oxidative Stress

7.1 Introduction

7.2 The ROS-Scavenging System in Cardiovascular Disease

7.2.1 Chemistry of Free Radical and Non-Radical Species

7.2.2 CVD-Related Conditions and Risk Factors and Their Association with Oxidative Stress

7.3 Types of ROS and Main Sources in CVD

7.3.1 Mitochondrial Electron Transport Chain

7.3.2 Nicotinamide Adenine Dinucleotide Phosphate Oxidases

7.3.3 Xanthine Oxidase

7.3.4 Lipoxygenases

7.3.5 Myeloperoxidase

7.3.6 Arachidonic Acid and P450 Hydroxylases

7.4 Maintenance of Redox Homeostasis

7.4.1 Antioxidants

7.4.2 ROS, Antioxidants, and Signal Transduction

7.4.3 Redox Regulation of Physiological Functions

7.5 Pharmacological Interventions

7.5.1 Drug-Induced Oxidative Stress

7.5.2 Experimental Therapeutic Agents against CVD

7.5.3 Antioxidants of Exogenous Source as Potential Therapeutic Targets

7.5.4 Antioxidants of Endogenous Source as Potential Therapeutic Targets

7.6 Conclusions and Future Trends

8. Enzymatic Amino Acid Deprivation Therapies Targeting Cancer

8.1 Introduction

8.2 Amino Acid Deprivation Enzymes

8.2.1 Arginine

8.2.2 Arginine Deiminase

8.2.2.1 Therapeutic uses

8.2.2.2 Structure and reaction mechanism

8.2.3 Arginase

8.2.3.1 Therapeutic uses

8.2.3.2 Structure and reaction mechanism

8.2.4 Asparagine

8.2.4.1 Therapeutic uses

8.2.4.2 Structure and reaction mechanism

8.2.5 Methionine

8.2.5.1 Therapeutic uses

8.2.5.2 Structure and reaction mechanism

8.3 Conclusions

9. Carboxylesterase Inhibitors: Relevance for Pharmaceutical Applications 349

9.1 Introduction

9.2 Structural Features and Catalytic Properties of CES

9.2.1 Structural Features of CES

9.2.2 The Catalytic Properties of CES

9.3 Tissue Distribution and Substrate Preference of Human CES

9.3.1 Tissue Distribution of Human CES

9.3.2 Substrate Preferences of Human CES

9.4 Biological Functions of CES and Applications of CES Inhibitors

9.5 Recent Advances on Discovery of CES Inhibitors

9.5.1 Reversible Inhibitors of Human CES

9.5.1.1 1,2-Diones

9.5.1.2 Benzene sulfonamides

9.5.1.3 Trifluoroketones

9.5.1.4 Acyl glucuronides

9.5.1.5 Triterpenoids

9.5.1.6 Flavonoids

9.5.1.7 Other CES inhibitors

9.5.2 Irreversible Inhibitors of Human CES

9.5.2.1 Carbamates

9.5.2.2 Organophosphates

9.6 Conclusion and Future Perspectives

10. Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases 397

10.1 Introduction

10.2 FAD: The Catalytic Cofactor

10.2.1 FAD Is Covalently Attached to MAO

10.2.2 FAD Is Modified by Irreversible Inhibitors

10.3 MAO Proteins

10.3.1 MAO Protein Expression and Activity

10.3.2 Structures and Active Sites

10.3.3 MAO Chemical Mechanism

10.3.4 Two Substrate Kinetics and Consequences for Amine Turnover

10.4 Substrate Specificity of these Promiscuous Enzymes

10.4.1 Neurotransmitter Metabolism

10.4.2 Metabolism of Biogenic Amines

10.4.3 Products from MAO Catalysis

10.5 Inhibition of MAO

10.5.1 Reversible Inhibitors of MAO

10.5.2 Examples of Tight Binding Reversible Inhibitors of MAO

10.5.3 Examples of Irreversible Inhibitors of MAO

10.6 Computational Innovation

10.6.1 Theoretical Elucidation of Mechanism

10.6.2 Data-Mining and Tools for Drug Discovery

10.7 Conclusion: The Future for MAO Inhibition in Multi-Target Drugs

11. Multi-Functional Monoamine Oxidase and Cholinesterase Inhibitors for the Treatment of Alzheimer’s Disease 427

11.1 Introduction: Alzheimer’s Disease

11.2 Cholinesterases: Isoforms and Function

11.3 Cholinergic Hypothesis of AD

11.4 Monoamine Oxidase: Isoforms and Function

11.4.1 Monoamine Oxidase A

11.4.2 Monoamine Oxidase B

11.4.3 Monoamine Oxidase in AD

11.5 Treatment of AD

11.5.1 Multi-Functional MAO and ChE Agents

11.5.1.1 Donepezil derivatives

11.5.1.2 Coumarin derivatives

11.5.1.3 Propargylated compounds

11.5.2 Miscellaneous Inhibitors

11.6 Conclusion

12. The Neurodegenerative Characteristics of Alzheimer’s Disease and Related Multi-Target Drug Design Studies

12.1 Introduction

12.2 Validated Targets and the Current Drugs Used for the Treatment of AD

12.3 Multi-Target Ligand Design Studies Based on the Neurodegenerative Characteristics of the Disease

12.3.1 Dual BACE1 and ACHE Inhibitors

12.3.2 Dual Inhibitors of Monoamine Oxidase and Cholinesterase

12.3.3 Dual Inhibitors of Cholinesterase and Aβ Aggregation

12.3.4 Cholinesterase Inhibitors and Antioxidants

12.3.5 Gamma Secretase Inhibitors

12.3.6 Dual Cholinesterase Inhibitors and Metal Chelators

12.4 Conclusion

13. Aldehyde Oxidases as Enzymes in Phase I Drug Metabolism

13.1 Introduction

13.2 Gene Organization and Phylogeny of AOX Enzymes

13.3 Overall Structure and Domain Architecture of hAOX

13.4 Structural Basis of Substrate and Inhibitor Binding

13.5 The Catalytic Mechanism of Human AOX1

13.6 Genetic Diversity Provided by Single-Nucleotide Polymorphisms

13.7 Relevance of AOX in Drug Metabolism and Cancer

13.8 Conclusions

14. Cytochrome P450 Enzymes for the Synthesis of Novel and Known Drugs and Drug Metabolites

14.1 Introduction

14.2 General Background on Cytochrome P450 Enzymes

14.3 Wild-Type CYP Enzymes in the Synthesis of Novel Drugs and Drug Metabolites

14.3.1 Bacterial CYP Enzymes

14.3.2 Yeast and Plant CYP Enzymes

14.3.3 Mammalian CYP Enzymes

14.4 Limitations

14.4.1 Substrate Diversity

14.4.2 Activity

14.4.3 Stability

14.5 CYP Engineering for Enhanced Activity, Stability, and Specificity to Overcome the Limitations

14.5.1 Bacterial CYP Enzymes

14.5.1.1 CYPBM3

14.5.1.2 CYP105 family

14.5.1.3 CYP106A2

14.5.1.4 CYP153A

14.5.1.5 CYP101A1

14.5.2 Plant CYP Enzymes

14.5.3 Mammalian CYP Enzymes

14.6 Advantages of Using CYP Enzymes for Drugs and Drug Metabolites Synthesis

14.6.1 Active Catalysts

14.6.2 Easy Availability and Diverse Substrate Selection

14.6.3 Generation of Higher Yields of Drugs

14.6.4 Development of New Antibiotic Drugs

14.6.5 Generation of Drug Metabolites

14.7 Conclusion and Future Prospects

15. Cytochromes P450, Cardiovascular Homeostasis and Disease

15.1 Introduction

15.2 CYP-Mediated Biosynthetic Pathways of Arachidonic Acid

15.3 CYPs and Pathophysiology of Cardiovascular Diseases

15.3.1 Atherothrombosis

15.3.2 Coronary Artery Disease

15.3.3 Hypertension

15.3.4 Renovascular Diseases

15.4 Promising Therapeutic Strategies in Vascular and Cardiovascular Diseases

15.4.1 Cyclooxygenase Inhibitors and Thromboxane Modulators in Atherosclerosis

15.4.2 EET Modulators in Vascular Dysfunctions

15.5 Conclusion

16. Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins

16.1 Introduction

16.2 Chemical Protein Knockdown Technology

16.2.1 SNIPERs (Specific and Non-Genetic Inhibitor of Apoptosis Protein [IAP]-Dependent Protein Erasers)

16.2.2 PROTACS (Proteolysis Targeting Chimeras)

16.3 Features of Protein Knockdown Technology

16.3.1 Comparison with Enzyme Inhibitors

16.3.2 Comparison with Genetic Knockdown Technologies

16.3.3 Comparison with “Mono-Ligand” Type Protein Degraders

16.3.4 Comparison with Therapeutic Antibodies

16.4 Prospect of Chemical Protein Knockdown Technology

16.4.1 Rational Design and Optimization of SNIPERs and PROTACs

16.4.2 Drug-Like Properties

16.4.3 Need for Development of a Novel E3 Ubiquitin Ligase Ligand

16.5 Conclusion

17. Resistance Mechanisms of Tumor Cells

17.1 Introduction

17.2 Development of Solid Tumors

17.3 Development of Hematological Tumors

17.4 General Treatment of Tumors and Patient Outcome

17.5 Concept of Cancer Stem Cells

17.6 Immunotherapies

17.7 Therapy Resistance Mechanisms

17.7.1 Multidrug Resistance

17.7.2 TP53 Mutations

17.7.3 Acquiring Stem Cell Features and Quiescence

17.7.4 Manipulating the Niche

17.7.5 Triggering Checkpoints

17.8 Summary

18. Biocatalytic Nanoreactors for Medical Purposes

18.1 Introduction

18.2 Enzymes of Medical Importance

18.2.1 Enzyme Deficiency Disorders

18.2.2 Enzymes for Cancer Therapy

18.2.3 Other Medically Relevant Enzymes

18.3 Nanobioreactors

18.3.1 Nanobioreactor Design Strategies

18.3.1.1 Liposomes and micelles

18.3.1.2 DNA nanostructures

18.3.1.3 Protein-based nanoparticles

18.3.1.4 Carbohydrate-based nanoparticles

18.3.2 Tissue Targeting

18.3.2.1 Passive targeting

18.3.2.2 Active targeting

18.4 Immunogenic Response and Masking

18.5 Conclusions

19. Computer-Aided Drug Design for the Identification of Multi-Target Directed Ligands in Complex Diseases: An Overview

19.1 Introduction to Multi-Target Drug Designing

19.1.1 Multi-Target Drug Designing and Its Role in Complex Diseases

19.1.2 Multi-Target Directed Ligands over Single-Target Directed Ligands, Multiple-Medication Therapy, and Multiple-Compound Medication

19.1.3 MTDD Trend in Research and Development

19.1.4 Role of Computer-Aided Drug Discovery in MTDD

19.1.5 In silico Testing Prior to Experimental Validation

19.2 Computational Techniques Involved in MTDD

19.2.1 Preliminary Studies for Initial Selection of Potential Ligands and Target Proteins

19.2.2 In silico Approaches in MTDD

19.2.2.1 Combinatorial approaches

19.2.2.2 Fragment-based or de novo design approaches

19.3 Conclusion

20. The Development of Improved Therapeutics through a Glycan-“Designer” Approach

20.1 Introduction

20.2 Types of Glycosylation

20.3 The Effect of Glycosylation on Peptides, Proteins and Other Therapeutics

20.3.1 Glycosylation of Antimicrobial Peptides

20.4 Optimizing Immunogenicity

20.4.1 T Cell Signaling

20.4.2 Antigen Presenting Cell Signaling and Activation

20.5 Rational Design of Glycotherapeutics

20.6 Conclusions

21. On Biocatalysis as Resourceful Methodology for Complex Syntheses: Selective Catalysis, Cascades and Biosynthesis

21.1 Introduction

21.2 Single-Step Conversions

21.3 Multi-Step Conversions and Cascades

21.4 Biosynthesis

21.4.1 Native Biosynthesis

21.4.2 Utilizing Biosynthesis Providing Derivatives

21.4.2.1 Semisynthesis

21.4.2.2 Altered Biosynthesis

21.4.2.3 Precursor-directed biosynthesis and mutasynthesis

21.4.2.4 Mutasynthesis

21.5 Conclusion

Index

 

 

 

An aparitie	25 Jun. 2019
Autor	Peter Grunwald
Dimensiuni	15.75 x 4.32 x 23.11 cm
Editura	CRC Press
Format	Hardcover
ISBN	9789814800617
Limba	Engleza
Nr pag	800