Innovations in Combating Infectious Diseases: Opportunities in therapeutics and diagnostics through application of proteomics, genomics, nanotechnology, and novel sources of lead generation

Infectious disease is not merely a problem of the past; despite significant breakthroughs achieved during the last century in the development of antibiotic, antiviral, and antiparasitic drugs and vaccines, the eradication or even control of many infectious diseases has not been accomplished. Of particular current concern are the problems of rapidly developing drug resistance, emerging disease, re-emerging disease, the threat of bioterrorism, and the speed of reaction to the appearance of virulent strains posing pandemic threats. Furthermore, the effective treatment of infectious diseases is dependent on accurate and rapid diagnosis, and this in itself can present significant challenges, especially in cases where the disease progression is poorly understood or has long asymptomatic latency (such as prion diseases).
Successful drugs and vaccines against infectious agents that put millions of people at risk have potentially lucrative markets. The key to developing those drugs is to understand the pathogenic process and gain insight into where and how it can best be interrupted. This report makes a detailed and comprehensive analysis of the cutting edge of research aiming to reveal how bacteria, viruses, fungi, and prions infect and affect their hosts. It also assesses the new technologies and techniques that are being used to design and develop the anti-infective drugs and diagnostic methods of the 21st century.

Key features of this report

This report presents a snapshot of how new technologies and approaches are being applied to the discovery of new drug targets, vaccine candidates, lead compounds, and novel delivery systems that will enhance diagnostics and therapeutics across the whole range of infectious diseases:
• How proteomics is being used to identify biomarkers for new diagnostics in infectious diseases
• How proteomics is being used to identify novel targets for drug discovery and vaccine development in infectious diseases
• The impact of genomics on the search for novel targets for infectious disease drug discovery
• Novel natural sources for lead generation in infectious diseases
• Lead optimization techniques relevant to infectious diseases
• How the application of nanobiotechnology is impacting on drug discovery and drug delivery in infectious diseases

Scope of this report

• Gain awareness of the most significant areas of unmet need for anti-infective drug development.
• Build knowledge of the most promising diagnostics research – ripe for commercialization – for MRSA and community-acquired infections, bacterial meningitis, periodontal disease, and innovative ways for predicting outcome in hepatitis infections.
• Discover how proteomics and genomics are making an increasing impact on drug development programs, and how important infectious agents can be tackled by drug and vaccine approaches.
• Identify the new opportunities for small and large biotechnology based companies to undertake vaccine development based on proteomic and genomic studies

Key Market Issues

• More accurate and rapid diagnostics will remain a pressing need combating prion diseases, sexually transmitted diseases, HIV, hospital-acquired infections and bioterrorism threats.
• Diagnostics is a big area that is ripe for more commercial development, particularly for diagnostic kits that are fast and simple to operates by unskilled personnel, making them amenable to the point-of-care use.
• Personalized medicine will remain a priority; drug treatments need to be more tailored and efficient with fewer side effects, less frequent dosing, and faster action..
• Using genomics to monitor and carry out surveillance of infectious disease will become more important and more necessary, so that new outbreaks, spread of disease, and danger of pandemics can be better monitored and predicted by global warning systems.
• The need to identify, monitor, and respond to bioterrorism will continue to drive research into lethal viral infections such as small pox and ebola, and bacterial diseases such as anthrax and plague.

Key findings from this report

• Drug development, vaccine development, and novel approaches to therapeutics are needed urgently for bacterial, viral, fungal, and prion diseases, which cause high morbidity and mortality in both the developing and the developed world.
• To date, there has been an intensive research effort to use proteomics to detect, identify, characterize, and validate biomarkers and protein signatures in diagnostics for many different infectious diseases but validation and commercialization has so far proved relatively elusive.
• Drug resistance, emerging infections and the threat of bioterrorism make the understanding of virulence factors and disease pathogenesis essential to form a springboard from which to launch drug discovery programs.
• Genomics is being applied to drug discovery across the spectrum of infectious diseases, whether they are caused by bacteria, viruses, fungi, parasites, or prions. Genomic data can be used in public health surveillance and monitoring of infectious diseases, particularly when there is a threat of a pandemic or bioterrorist attack.
• Novel sources of lead compounds to screen against newly discovered targets are much needed; natural sources have already provided the starting point for several successful anti-infectives, and many sources remain to be explored.

Key questions answered

• Which areas of drug development in infectious disease could have the greatest impact?
• How can the relatively new technology of proteomics be used to develop leads for drug development?
• How are proteomic techniques being used in the design and production of modern diagnostic tools for infectious diseases?
• How are genomic technologies changing the way lead compounds are generated and providing ideas for innovative targeted drugs?
• In which bacteria, viral, fungal and prion diseases are fundamental research efforts showing the most potential for identifying compounds suitable for drug development?



Report Highlights

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Table of Contents
Innovations in Combating Infectious Diseases
Executive summary 12
The need for new therapeutic approaches in infectious diseases 12
Proteomics in the design of novel diagnostics for infectious diseases 12
Proteomic methods in infectious disease drug discovery 14
Genomics and its impact on drug discovery in infectious diseases 15
Natural sources of drug leads for infectious diseases 16
Lead optimization in infectious disease drug discovery 17
Applications of nanotechnology in infectious diseases 17
Chapter 1 The need for new therapeutic approaches in infectious diseases 20
Summary 20
Introduction 20
Why do we need continuing drug development? 20
Major areas of unmet need in infectious disease 21
Report scope 22
Chapter 2 Proteomics in the design of novel diagnostics for infectious diseases 24
Summary 24
Introduction 25
An overview of techniques in proteomics 26
Separation techniques 28
Two-dimensional gel electrophoresis (2D-GE) 28
Separation using SELDI Protein Chip technology 30
Identification techniques 31
Mass spectrometry 31
Bottom up and top down techniques 32
Targeted proteomics using western blots and MS 33
Antibody and aptamer microarray technology in proteomics 33
Allied technology: glycan arrays 34
Limitations of proteomic techniques 34
Limitations of MALDI-TOF 34
The need to be aware of artifacts 35
The limitations of shotgun proteomics 36
MALDI approaches – profiling and imaging 37
Protein, antibody, and aptamer arrays 38
Diagnostics in infectious diseases using proteomic techniques 39
Bacterial infections, proteomics, and diagnosis 40
MRSA and community- and hospital-acquired infections 40
Diagnosing bacterial meningitis and conjunctivitis 43
Faster and easier diagnosis of tuberculosis 44
Proteomics in the diagnosis of periodontal disease 45
Proteomics in the detection of bacteria that pose bioterrorist threats 46
Using proteome microarrays to identify plague 46
Diagnosis of anthrax using the host blood proteome 47
Parasitic infections, proteomics, and diagnosis 47
Developing diagnostic biomarkers for parasitic infections 48
Proteomic diagnostics for fungal infections 51
Proteomics in the detection of viral infections 53
SARS diagnosis using proteomics 54
Hepatitis prognosis using proteomics 54
New diagnostics for prion diseases 56
Conclusions 61
Chapter 3 Proteomic methods in infectious disease drug discovery 64
Summary 64
Introduction 65
Proteomics in target identification and lead discovery in infectious diseases 65
Using proteomics in drug discovery for parasitic diseases 65
Malaria – using proteomics to map parasitic gene expression 65
Liver fluke infections 68
Echinococcus multilocularis 69
Leishmaniasis 69
Entamoeba histolytica 69
Proteomics and antiviral discovery 70
HIV 70
Influenza 70
Hepatitis B 71
Proteomics in the discovery of novel antibacterial drug targets 71
Drug discovery for nosocomial infections 71
Targeting bacteria that affect the gut 73
Applying proteomics to rare bacterial diseases 74
Proteomics and drug discovery for bacterial meningitis 75
Proteomics and drug discovery in tuberculosis 76
Potential therapeutics for bioterrorist threats 77
Proteomics in antifungal drug discovery 77
Proteomics in the generation of new vaccine candidates 79
Antibacterial vaccines 79
Towards a new vaccine for tuberculosis 79
Antibiotic strains of Staphylococcus aureus 81
Clostridium difficile 81
Fungal vaccines 83
Parasitic vaccines 84
Leishmania amastigotes 84
Toxoplasma gondii 84
Schistosomiasis 84
Malaria 85
Viral vaccines 85
Proteomics and HIV vaccine approaches 86
Influenza vaccine strategies 86
Conclusions 87
Chapter 4 Genomics and its impact on drug discovery in infectious diseases 90
Summary 90
Introduction 91
Using genomics to identify new drug targets in infectious diseases 91
Using genomics to target pathogen factors 93
Ligand-based chemogenomic approaches 93
Using genomics to target host factors 95
Novel genomic approaches to therapeutics in infectious diseases 95
RNA interference 95
Ribozymes and flexizymes 96
Replicons 96
Genomics in antiviral drug discovery 97
Genomics and influenza 97
Background to influenza 97
Key development areas 98
How genomics can be applied 99
Genomics and HIV 99
Background to HIV 99
Key development areas 100
Genomics and flavivirus infection 101
Background to flaviviruses 101
Key development areas 101
Genomics and hepatitis C 102
Background to hepatitis C 102
Key development areas 103
Genomics and emerging viral disease 105
SARS-associated coronavirus 106
Nipah virus 107
Dengue 107
Genomics in antibacterial drug discovery 108
General approaches to the discovery of new antibiotics 109
Targeting metabolic networks 109
Genomics in antiparasitic drug discovery 110
Malaria 110
In silico profiling and novel antimalarial candidates 111
Targeting host cell factors 112
Evolutionary patterning 112
Kinetoplastid diseases 114
Toxoplasmosis 114
Schistosomiasis 115
Key development areas 115
Genomic characterization of parasitic pathogens 116
Trypanosomatids 117
Malaria 117
Schistosomiasis 117
Genomics in antifungal drug discovery 118
Genomic insights into prion diseases 119
Genomics in epidemiological surveillance and monitoring 119
Genomic strategies for designing novel infectious disease vaccines 120
Terrorist activity with bioagents: genomic and combined strategies for control 122
Conclusions 123
Chapter 5 Natural sources of drug leads for infectious diseases 126
Summary 126
Introduction 127
Drugs from natural sources worldwide 129
Asia and Africa Science Platform Program 130
Japan–China Joint Medical Workshop on Drug Discoveries and Therapeutics
2008 130
Drugs from China 132
Drugs from natural sources: research in other developing countries 133
Yemen 133
Cameroon 133
Kenya 133
Nigeria 134
Brazil 134
Peru 134
Antibiotics from natural sources 135
Antibacterials from plants 136
Antimicrobials from endophytes 136
Antimicrobials from other sources 138
Antiviral drugs from natural sources 139
Potential of phenolics of natural origin as anti-HIV agents 140
Medicinal plant extracts and activity against herpes simplex 140
Effect of sulfated astragalus polysaccharide on the cellular infectivity of infectious bursal disease virus 140
Antiviral compound derived from the plant Melia azedarach 141
Antifungal drugs from natural sources 141
Antifungal agents derived from plants 141
Activity of isoxazolidinone-containing compounds in the treatment of serious mycoses 141
Antiparasitic agents from natural sources 142
Artemisinin 142
Other antimalarial drug candidates from natural sources 143
Plant-derived antimalarial agents: new leads and efficient
phytomedicines 143
Cytotoxic and antiplasmodial compounds from the roots of
Strophioblachia fimbricalyx 144
Antiplasmoidal alkaloids from Cassia siamea 144
Marine actinomycetes against human malaria 144
Non-malarial parasitic diseases: leishmania and trypanosomes 144
Biosurfactants and derivation from natural sources 145
Potential applications of biosurfactants in medicine 145
Probiotic bacteria and biosurfactants for nosocomial infection control 145
Antimicrobial biosurfactants from marine Bacillus circulans 145
Pseudomonas aeruginosa rhamnolipids disperse Bordetella
bronchiseptica biofilms 145
Chapter 6 Lead optimization in infectious disease drug discovery 148
Summary 148
Introduction 149
What is lead optimization? 149
How is lead optimization conducted? 149
Lead optimization is a cyclical process 150
New drugs for old 151
Lead optimization can make or break drug discovery 152
The outcome of the lead optimization process 152
Techniques used in lead optimization 153
Lead optimization in infectious diseases 155
In silico tools 155
Using in silico tools in drug discovery for tuberculosis 155
Using in silico tools in drug discovery for malaria 157
Using in silico tools in HIV drug discovery 158
High content cellular imaging in infectious diseases 159
Application to bacterial diseases 159
Toxicogenomics-based assays in infectious diseases 160
What is the difference between toxicogenetics and toxicogenomics? 161
Genetic susceptibility factors in infectious diseases 162
Crystallographic approaches in infectious diseases 162
Antibiotic drug discovery 162
HIV drug discovery 163
Intelligent design in infectious diseases 164
Partnerships, databases, and networks 165
The TDR Drug Targets Database 165
TDR Activities 166
TDR achievements and goals 166
The Helminth Drug Initiative 167
HDI activities 167
HDI achievements and goals 167
The Drugs for Neglected Diseases initiative (DNDi) 167
DNDi achievements to date 168
Conclusions 169
Chapter 7 Applications of nanotechnology in infectious diseases 172
Summary 172
Introduction 173
The use of nanotechnology in diagnosis 175
Quantum dot probes 175
Synthetic polymers 176
Nanochips 176
The use of nanotechnology in novel therapeutics for infectious diseases 176
Novel delivery methods for antibiotics 177
Using bacteriophages to deliver drugs 177
Targeting of bacteriophage systems using polymeric nanostructures 178
Aerosol delivery systems 179
Photodynamic therapy systems 179
Nanoemulsions and nanoparticles 180
Biofilms 181
Biofilm infections in cystic fibrosis 182
Biofilm infections related to catheters 183
Biofilm infections on prosthetic devices 183
Novel therapeutic development strategies 184
Peptide therapeutics 184
Use of nanotechnology to combat tuberculosis 184
Use nanotechnology to combat pneumonia 185
Use of nanotechnology to combat malaria 185
Use of nanotechnology to combat Sin Nombre hantavirus infection 186
Using nanotechnology to target fungal infections 186
Candidiasis 186
New nanovaccine strategies for infectious diseases 187
Delivering nanovaccines by injection 187
Mucosal delivery 188
Gene vaccines 189
Novel drug delivery using nanotechnology 190
Nanotubes 190
Polyphosphazenes and delivery of vaccine antigens 192
Solid lipid nanoparticles 192
Conclusions 192
Appendix 195
Bibliography 195
Chapter 1 195
Chapter 2 196
Chapter 3 203
Chapter 4 209
Chapter 5 220
Chapter 6 227
Chapter 7 232
Glossary 240
Index 249
List of Figures
Figure 2.1: Overview of proteomics 26
Figure 2.2: Standard proteomic approaches 27
Figure 2.3: Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) workflow 29
Figure 2.4: Example of SELDI-TOF workflow 30
Figure 2.5: Sites of the body usually affected by MSRA infections 41
Figure 2.6: Pulmonary TB 44
Figure 2.7: Trichonomas vaginalis in a Pap smear 51
Figure 3.8: Distribution of proteins produced at different life-cycle stages of Plasmodium falciparum 67
Figure 3.9: Clostridium difficile colonies on a blood agar plate 82
Figure 4.10: Structure–activity relationship homology flowchart 94
Figure 4.11: Novel antiviral strategies based on the HCV life cycle 104
Figure 4.12: Target identification via pathogen and host genome sequencing 106
Figure 4.13: Emergence of MRSA in the US 108
Figure 4.14: Phylogenetic reconstruction based on orthologous glycerol kinase sequences 113
Figure 4.15: Timeline of antifungal drug development 118
Figure 6.16: Summary of techniques used in lead optimization 154
Figure 6.17: Attrition rates and current drug R&D pipeline for neglected diseases 169
Figure 7.18: Relationship of nanobiotechnology to nanomedicine and other biotechnologies 173
Figure 7.19: Schematic representation of a drug-carrying bacteriophage 178
Figure 7.20: Biofilm maturation 181
Figure 7.21: Single-walled carbon nanotube bundles (SWNT) with adsorbed antibody presenting that antibody to T-cells 191
List of Tables
Table 2.1: Advantages and disadvantages of SELDI 31
Table 2.2: Advantages and disadvantages of MALDI 38
Table 2.3: Deaths in the UK annually since 1990 from CJD of all known causes 57


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