The Carbonic Anhydrases: Current and Emerging Therapeutic Targets

Dedication to Richard Tashian
Preface
Contents
1 The Carbonic Anhydrases in Health and Disease
	References
2 Carbonic Anhydrase Isozymes as Diagnostic Biomarkers and Therapeutic Targets
	2.1 Short Introduction of Mammalian Carbonic Anhydrases
	2.2 CA II as a Biomarker
	2.3 CA IX as a Biomarker
	2.4 CA IX Immunoassay Data
	2.5 CA XII in Cancer
	2.6 Carbonic Anhydrases as Therapeutic Targets
	2.7 Concluding Remarks
	References
3 Targeting Carbonic Anhydrases in Cardiovascular and Pulmonary Disease
	3.1 Introduction
	3.2 Carbonic Anhydrase Isozymes and Activity in the Cardiopulmonary System
	3.3 Effects of CA Inhibitors Independent of CA Inhibition
	3.4 CA Functions in the Normal Heart
		3.4.1 CO2 Elimination
		3.4.2 Cardiac pH Homeostasis
		3.4.3 Metabolism-Perfusion Matching
		3.4.4 Fatty Acid/Lactate Uptake
		3.4.5 Myocardial Contractility and Calcium Mobilization
	3.5 CA Functions in the Normal Lung
		3.5.1 Alveolar Carbon Dioxide Elimination
		3.5.2 Lung Fluid Exchange and pH Regulation
		3.5.3 Ventilation-Perfusion Matching
		3.5.4 Pleural Fluid Composition and Turnover
	3.6 Carbonic Anhydrase Inhibitors and Cardiovascular Disease
		3.6.1 Systemic Hypertension
		3.6.2 Cardiac Hypertrophy and Heart Failure
		3.6.3 Coronary Artery Disease and Myocardial Infarction
	3.7 Carbonic Anhydrase Inhibitors in Pulmonary Disease
		3.7.1 Chronic Obstructive Pulmonary Disease (COPD)
		3.7.2 Chronic Cough
		3.7.3 Pulmonary Hypertension (PH)
		3.7.4 Lung Ischemia–Reperfusion Injury
	3.8 Conclusions
	References
4 Carbonic Anhydrase Inhibitors in Ophthalmology: Glaucoma and Macular Oedema
	4.1 Introduction
	4.2 Carbonic Anhydrase Inhibitors in Glaucoma
		4.2.1 Systemic Carbonic Anhydrase Inhibitors
		4.2.2 Topical Carbonic Anhydrase Inhibitors
		4.2.3 Carbonic Anhydrase Inhibitors in Ocular Perfusion
	4.3 Carbonic Anhydrase Inhibitors in Macular Oedema
		4.3.1 Systemic Carbonic Anhydrase Inhibitors
		4.3.2 Topical Carbonic Anhydrase Inhibitors
	References
5 Targeting Carbonic Anhydrase Isozymes in the Treatment of Neurological Disorders
	5.1 Expression and Function of Enzymatically Active Carbonic Anhydrases in the Nervous System
	5.2 CA Inhibitors in the Treatment of Neurological Diseases
	5.3 CA Inhibitors in the Treatment of Acute High-Altitude Illness
	5.4 CA Inhibitors in the Treatment of Pseudotumor Cerebri
	5.5 CA Inhibitors in the Treatment of Brain Edema
	5.6 CA Inhibitors in the Treatment of Epilepsy
	5.7 Carbonic Anhydrase-Related Proteins (CARPs)
	5.8 Localization and Role of CARP VIII
	5.9 Distribution and Role of CARP X
	5.10 Distribution and Role of CARP XI
	5.11 Concluding Remarks
	References
6 Potential of Carbonic Anhydrase Inhibitors in the Treatment of Oxidative Stress and Diabetes
	6.1 Introduction
	6.2 Oxidative Stress and Diabetes
	6.3 Retinal Pericytes and Metabolic Activity
	6.4 Metabolic Activity, Oxidative Stress, and Diabetic Retinopathy
	6.5 Carbonic Anhydrases
	6.6 Mitochondrial Carbonic Anhydrases and Oxidative Stress
	6.7 Carbonic Anhydrase Inhibitors and Prevention of Diabetic Retinopathy
	6.8 Conclusions
	References
7 An Overview of Carbonic Anhydrase-Related Neoplasms
	7.1 Introduction
	7.2 Expression of Cytoplasmic CA Isoforms in Neoplasms
	7.3 Expression of Mitochondrial CA Isoforms in Cancer
	7.4 Expression of Membrane-Bound and Secreted CA Isoforms in Cancer
	7.5 Expression of Inactive CA Isoforms in Cancer
	7.6 Carbonic Anhydrase-Related Neoplasms
	7.7 Conclusions
	References
8 Carbonic Anhydrase IX Interactome and the Regulation of Cancer Progression
	8.1 Tumour Microenvironment and Hypoxia
	8.2 CAIX—regulation, Protein and Function
	8.3 Overview of the CAIX Interactome
	8.4 CAIX in Metastasis
		8.4.1 CAIX and Cell–cell De-Adhesion
		8.4.2 CAIX and Cell Migration
		8.4.3 Invadopodia-Mediated Cell Invasion
	8.5 Amino Acid Transporters and CAIX
	8.6 CAIX and Unfolded Protein Response
	8.7 Summary and Therapeutic Implications
	References
9 Carbonic Anhydrase IX: Current and Emerging Therapies
	9.1 Introduction
	9.2 Carbonic Anhydrase IX Imaging
		9.2.1 CAIX Imaging in RCC
		9.2.2 CAIX Imaging in Non-RCC
	9.3 Intraoperative Imaging
	9.4 CAIX-Directed Radioimmunotherapy
	9.5 Carbonic Anhydrase IX Immunotherapy
	9.6 Conclusion and Future Perspectives
	References
10 Carbonic Anhydrase Inhibitors: Designing Isozyme-Specific Inhibitors as Therapeutic Agents
	10.1 Introduction: Classical CA Inhibitors (CAIs)
	10.2 CA Inhibition Mechanisms and the Drug Design
	10.3 Strategies for Obtaining Isoform-Selective CAIs
	10.4 Conclusions
	References
11 Carbonic Anhydrase Inhibitors: Identifying Therapeutic Cancer Agents Through Virtual Screening
	11.1 Virtual Screening in Drug Discovery
	11.2 Virtual Screening Studies Identifying Novel Carbonic Anhydrase Inhibitors
	11.3 Retrospective Virtual Screening Studies Using Carbonic Anhydrases as Target Receptors
	References
12 Targeting Carbonic Anhydrase IX in Tumor Imaging and Theranostic Cancer Therapy
	12.1 Introduction
	12.2 Targeting CA-IX as a Biomarker of Tumor Hypoxia
	12.3 Methods for Detecting Tumor Hypoxia
	12.4 CA-IX Expression in Clear Cell Renal Cell Carcinoma
	12.5 Monoclonal Antibodies
		12.5.1 Imaging with G250/cG250
		12.5.2 Radioimmunotherapy with G250/cG250
		12.5.3 Dual Modality Imaging with cG250
	12.6 Peptides and Affibodies
	12.7 Small Molecule Inhibitors
		12.7.1 Net Charge
		12.7.2 Multivalence and Size
		12.7.3 Radiometal Chelator Complex
	12.8 Perspectives and Conclusion
	References
Index