Pharmaceutical Biocatalysis

Fundamentals, Enzyme Inhibitors, and Enzymes in Health and Diseases

Peter Grunwald

• Publisher: Jenny Stanford Publishing
• Year: 2019
• Print ISBN: 9789814800617
• eBook ISBN: 9781000021288
• Topic: Médecine
• Subtopic: Biotechnologie en médecine

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.

Chapter 1

Pharmaceuticals: Some General Aspects

Peter Grunwald

Department of Physical Chemistry, University of Hamburg, D-20146 Hamburg, Germany

[email protected]

1.1 Introduction

In this chapter, apart from brief general remarks, some aspects of enzymes and enzyme inhibitors employed for therapeutic applications will be discussed. The topics are, among others, the following:

• The world market of these drugs

• Regulatory authorities (mainly the US FDA and the EMA)

• Quality standards

• Rare diseases and orphan drugs

• Therapeutic enzymes and enzyme inhibitors

• Cost of drug development and therapies

• Future developments

The term “drug” is used here in connection with recombinant therapeutic proteins (for the world market of therapeutic proteins, see Research and Markets, 2016) as well as chemically synthesized small molecules that have been approved for the treatment and prevention of diseases. Not included are diagnostic imaging agents as, e.g., Netspot (detection of rare neuroendocrine tumors) or Axumin (detection of recurrent prostate cancer) both approved by the FDA in 2016, and other compounds used for diagnostic purposes. The targets of small molecule drugs are proteins to which they bind to exert therapeutic efficacy; enzymes involved in drug metabolism are not defined here as drug target. The WHO Collaborating Centre for Drug Statistics Methodology classifies drugs by The Anatomical Therapeutic Chemical (ATC) Classification System (ATC and ATCvet) with respect to the organ or system, on which they act, their therapeutic, pharmacological, and chemical properties, etc., including, e.g., defined daily drug doses (WHOATC 2018).

1.2 General Remarks

Enzyme inhibitor drugs are used to treat chronic diseases and disorders such as cardiovascular diseases (angina and myocardial infarction, heart failure, hypertensive heart and rheumatic heart disease, etc.), gastrointestinal diseases, Diabetes Type 2, pain, fever, inflammation, neurodegenerative diseases such as Parkinson’s and Alzheimer’s, asthma and COPD, psoriasis and psoriatic arthritis, different infectious diseases (trypanosomiasis, leishmaniasis, tuberculosis, malaria, acquired immunodeficiency syndrome, etc.), a variety of different types of cancers (see below), some of the rare lysosomal storage diseases, life style related conditions (erectile dysfunction, benign prostatic hyperplasia, alopecia) and many others.

Pharmaceutical enzymes may be categorized as enzymes in replacement therapy, enzymes in cancer treatment, enzymes for fibrinolysis, enzymes to cure digestive disorders and enzymes that are used topically for various treatments (Yari et al., 2017). Modern DNA technology together with other approaches such as PEGlation or glycoengineering generates enzymes with extended half-life and reduced or no immunogenicity.

The Food and Drug Administration (FDA or USFDA) a federal agency of the United States Department of Health and Human Services is—together with several FDA organizations among them the Center for Drug Evaluation and Research (CDER)—responsible for controlling apart from cosmetics, animal foods and feed, tobacco products, dietary supplements and veterinary products, new drug application (new molecular entities, NMEs) and prescription, over-the-counter pharmaceutical drugs, generic drugs, vaccines, biopharmaceuticals, etc. An NME is a drug with an active moiety that is approved by the FDA as a single ingredient drug or as part of a combination product or marketed in the US for the first time; hence, treatment with an NME is often tantamount to a new therapy for patients.

Its European counterpart is the European Medicines Agency (EMA), which recently moved from London to Amsterdam. The function of the EMA (2017, 2018) is to protect “public and animal health in 28 EU Member States, as well as the countries of the European Economic Area, by ensuring that all medicines available on the EU market are safe, effective and of high quality; the EMA serves a market of over 500 million people living in the EU.” A European medicines regulatory network aims among others on reducing the administrative burden through the centralized authorization procedure, translating into medicines reaching patients faster. The EMA has a number of committees for Medicinal Products for Human Use, Pharmacovigilance Risk Assessment, for Medicinal Products for Veterinary Use, for Orphan Medicinal Products, Herbal Medicinal Products, for Advanced Therapies, and a Paediatric Committee.

According to more recent developments, the FDA offers an Expedited Program for speeding up the availability of drugs that treat serious diseases: Fast track (the aim is to facilitate the development, and expedite the review of drugs to treat serious conditions, filling an unmet medical need), breakthrough therapy (substantial improvement over available therapy), priority review (FDA’s goal is to take action on an application within 6 months), and accelerated approval (allows drugs to be approved based on a surrogate endpoint) are the 4 ways applied singly or in conjunction in which the FDA cooperates with the industry (see Table 1.1) in developing drugs (FDA, 2018; 2018a). This resulted in an increase of the speed at which new drugs are and have been developed and reviewed, and is expressed by the fact that 78% and 87% of drug applications were approved by the FDA in the first review cycle in 2014 and 2015, respectively, compared with just 58% between 2008 and 2012 (Tworkoski, 2016).

Table 1.1 Drugs approved by the FDA in 2016

API	Drug Name	FDA-approved use	Expedited program	Company
Elbasvir & grazoprevir	Zepatier	Chronic hepatitis C virus	BT	MSD SHARP & DOHME GMBH
Brivaracetam	Briviact	Partial onset seizures		UCB (Union Chimique Belge)
Obiltoxaximab	Anthim	Inhalational anthrax		Elusys Therapeutics, Inc.
Ixekizumab	Taltz	Plaque psoriasis		Eli Lilly & Company
Reslizumab	Cinqair	Severe asthma		Teva Pharmaceuticals
Defibrotide sodium	Defitelio	Hepatic veno-occlusive disease	PR, OD	Jazz Pharmaceuticals
Venetoclax	Venclexta	Chronic lymphocytic leukemia	AA, BT, PR, OD	AbbVie Inc.
Pimavanserin	Nuplazid	Hallucinations & delusions	BT, PR	Acadia Pharmaceuticals Inc.
Atezolizumab	Tecentriq	Urothelial carcinoma	AA, BT, PR	Genentech
Daclizumab	Zinbryta	Multiple sclerosis		Biogen, Inc.
Obeticholic acid	Ocaliva	Chronic liver disease	AA, FT, OD	Intercept Pharmaceuticals, Inc.
Fluciclovine F 18; imaging agent	Axumin	To detect recur-rent prostate cancer		Blue Earth Diagnostics, Ltd.
Ga 68 dotatate; imaging agent	NETSPOT	To detect neuroendocrine tumors	PR, OD	Advanced Accelerator Applications USA, Inc.
Sofosbuvir & velpatasvir	Epclusa	All six major forms of hepatitis C virus	PR	Gilead Sciences, Inc.
Lifitegrast ophthalmic solution	Xiidra	Dry eye disease		Shire US Inc.
Lixisenatide	Adlyxin	Improve glycemic control		Sanofi-Aventis U.S. LLC
Eteplirsen	Exondys 51	Duchenne muscular dystrophy	AA, FT, PR, OD	Sarepta Therapeutics
Olaratumab	Lartruvo	Soft tissue sarcoma	AA, BT, FT, PR, OD	Eli Lilly & Company
Crisaborole	Eucrisa	Atopic dermatitis		Anacor Pharmaceuticals, Inc.
Bezlotoxumab	Zinplava	Decrease the risk of Clostridium difficile infection		Merck Sharp & Dohme Corp.
Rucaparib	Rubraca	Ovarian cancer	AA, BT, PR, OD	Foundation Medicine, Inc.
Nusinersen	Spinraza	Spinal muscular atrophy	FT, PR, OD	Ionis Pharmaceuticals
Note: AA, Accelerated approval; PR, Priority review status, BT, Breakthrough therapy designation; FT, Fast track designation; OD, Orphan drug designation; API, Active Pharmaceutical ingredient.

The understanding of cancer pathogenesis has significantly improved in the recent past which has led to new therapeutic concepts such as targeted agents designed to inhibit molecular pathways that are crucial for tumor growth, or immunotherapeutic approaches (Vanneman and Dranoff, 2012; Gotwals et al., 2017; Banchereau and Palucka, 2018) including immune checkpoint inhibitors (Dine et al., 2017). Another recent example is Yescarta, a chimeric antigen receptor (CAR) T cell therapy, approved as the second gene therapy by the FDA for treating diffuse large B-cell lymphoma (DLBCL, the most common type of non-Hodgkin lymphoma; FDA, 2018c); Yescarta has received the orphan drug status (see next section). This has led to an improved survival of patients suffering from certain types of cancer and finds expression, too, in a trend towards an increased share of oncologic drugs as part of the number of drugs approved per year as shown in the following figure (see also Centerwatch, 2018).

1.3 Orphan Drugs and Rare Diseases

According to the European Medicines Agency the number of rare/orphan diseases is between 5,000 and 8,000, and 27 million to 36 million patients in the EU are suffering from such diseases of which most (~80%) are of genetic origin. The NORD’s (National Organization for Rare Disorders, Inc.) database contained details for more than 1,200 rare diseases by 2018. The orphan drug status has been introduced in various...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Preface
• 1. Pharmaceuticals: Some General Aspects
• 2. Use of Enzymes in the Downstream Processing of Biopharmaceuticals
• 3. Therapeutic Use of Carbonic Anhydrase Inhibitors and Their Multiple Drug Interactions
• 4. Fibrinolytic Enzymes for Thrombolytic Therapy
• 5. Role of Engineered Proteins as Therapeutic Formulations
• 6. Synthesis of Bioactive Peptides for Pharmaceutical Applications
• 7. Cardiovascular Disease and Oxidative Stress
• 8. Enzymatic Amino Acid Deprivation Therapies Targeting Cancer
• 9. Carboxylesterase Inhibitors: Relevance for Pharmaceutical Applications 349
• 10. Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases 397
• 11. Multi-Functional Monoamine Oxidase and Cholinesterase Inhibitors for the Treatment of Alzheimer’s Disease 427
• 12. The Neurodegenerative Characteristics of Alzheimer’s Disease and Related Multi-Target Drug Design Studies
• 13. Aldehyde Oxidases as Enzymes in Phase I Drug Metabolism
• 14. Cytochrome P450 Enzymes for the Synthesis of Novel and Known Drugs and Drug Metabolites
• 15. Cytochromes P450, Cardiovascular Homeostasis and Disease
• 16. Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
• 17. Resistance Mechanisms of Tumor Cells
• 18. Biocatalytic Nanoreactors for Medical Purposes
• 19. Computer-Aided Drug Design for the Identification of Multi-Target Directed Ligands in Complex Diseases: An Overview
• 20. The Development of Improved Therapeutics through a Glycan-“Designer” Approach
• 21. On Biocatalysis as Resourceful Methodology for Complex Syntheses: Selective Catalysis, Cascades and Biosynthesis
• Index