SPI Infoamtion

Table of Contents

Executive summary

The need for new therapeutic approaches in infectious diseases
Proteomics in the design of novel diagnostics for infectious diseases
Proteomic methods in infectious disease drug discovery
Genomics and its impact on drug discovery in infectious diseases
Natural sources of drug leads for infectious diseases
Lead optimization in infectious disease drug discovery
Applications of nanotechnology in infectious diseases

Chapter 1 The need for new therapeutic approaches in infectious diseases

Summary
Introduction

Why do we need continuing drug development?

Major areas of unmet need in infectious disease

Report scope

Chapter 2 Proteomics in the design of novel diagnostics for infectious diseases

Summary
Introduction
An overview of techniques in proteomics

Separation techniques

Two-dimensional gel electrophoresis (2D-GE)

Separation using SELDI Protein Chip technology

Identification techniques

Mass spectrometry

Bottom up and top down techniques

Targeted proteomics using western blots and MS

Antibody and aptamer microarray technology in proteomics

Allied technology: glycan arrays

Limitations of proteomic techniques

Limitations of MALDI-TOF

The need to be aware of artifacts

The limitations of shotgun proteomics

MALDI approaches - profiling and imaging

Protein, antibody, and aptamer arrays

Diagnostics in infectious diseases using proteomic techniques

Bacterial infections, proteomics, and diagnosis

MRSA and community- and hospital-acquired infections

Diagnosing bacterial meningitis and conjunctivitis

Faster and easier diagnosis of tuberculosis

Proteomics in the diagnosis of periodontal disease

Proteomics in the detection of bacteria that pose bioterrorist threats

Using proteome microarrays to identify plague

Diagnosis of anthrax using the host blood proteome

Parasitic infections, proteomics, and diagnosis

Developing diagnostic biomarkers for parasitic infections

Proteomic diagnostics for fungal infections

Proteomics in the detection of viral infections

SARS diagnosis using proteomics

Hepatitis prognosis using proteomics

New diagnostics for prion diseases

Conclusions

Chapter 3 Proteomic methods in infectious disease drug discovery

Summary
Introduction
Proteomics in target identification and lead discovery in infectious diseases

Using proteomics in drug discovery for parasitic diseases

Malaria - using proteomics to map parasitic gene expression

Liver fluke infections

Echinococcus multilocularis

Leishmaniasis

Entamoeba histolytica

Proteomics and antiviral discovery

HIV

Influenza

Hepatitis B

Proteomics in the discovery of novel antibacterial drug targets

Drug discovery for nosocomial infections

Targeting bacteria that affect the gut

Applying proteomics to rare bacterial diseases

Proteomics and drug discovery for bacterial meningitis

Proteomics and drug discovery in tuberculosis

Potential therapeutics for bioterrorist threats

Proteomics in antifungal drug discovery

Proteomics in the generation of new vaccine candidates

Antibacterial vaccines

Towards a new vaccine for tuberculosis

Antibiotic strains of Staphylococcus aureus

Clostridium difficile

Fungal vaccines

Parasitic vaccines

Leishmania amastigotes

Toxoplasma gondii

Schistosomiasis

Malaria

Viral vaccines

Proteomics and HIV vaccine approaches

Influenza vaccine strategies

Conclusions

Chapter 4 Genomics and its impact on drug discovery in infectious diseases

Summary
Introduction
Using genomics to identify new drug targets in infectious diseases

Using genomics to target pathogen factors

Ligand-based chemogenomic approaches

Using genomics to target host factors

Novel genomic approaches to therapeutics in infectious diseases

RNA interference

Ribozymes and flexizymes

Replicons

Genomics in antiviral drug discovery

Genomics and influenza

Background to influenza

Key development areas

How genomics can be applied

Genomics and HIV

Background to HIV

Key development areas

Genomics and flavivirus infection

Background to flaviviruses

Key development areas

Genomics and hepatitis C

Background to hepatitis C

Key development areas

Genomics and emerging viral disease

SARS-associated coronavirus

Nipah virus

Dengue

Genomics in antibacterial drug discovery

General approaches to the discovery of new antibiotics

Targeting metabolic networks

Genomics in antiparasitic drug discovery

Malaria

In silico profiling and novel antimalarial candidates

Targeting host cell factors

Evolutionary patterning

Kinetoplastid diseases

Toxoplasmosis

Schistosomiasis

Key development areas

Genomic characterization of parasitic pathogens

Trypanosomatids

Malaria

Schistosomiasis

Genomics in antifungal drug discovery
Genomic insights into prion diseases
Genomics in epidemiological surveillance and monitoring
Genomic strategies for designing novel infectious disease vaccines

Terrorist activity with bioagents: genomic and combined strategies for control

Conclusions

Chapter 5 Natural sources of drug leads for infectious diseases

Summary
Introduction
Drugs from natural sources worldwide

Asia and Africa Science Platform Program

Japan-China Joint Medical Workshop on Drug Discoveries and Therapeutics 2008

Drugs from China

Drugs from natural sources: research in other developing countries

Yemen

Cameroon

Kenya

Nigeria

Brazil

Peru

Antibiotics from natural sources

Antibacterials from plants

Antimicrobials from endophytes

Antimicrobials from other sources

Antiviral drugs from natural sources

Potential of phenolics of natural origin as anti-HIV agents

Medicinal plant extracts and activity against herpes simplex

Effect of sulfated astragalus polysaccharide on the cellular infectivity of

infectious bursal disease virus

Antiviral compound derived from the plant Melia azedarach

Antifungal drugs from natural sources

Antifungal agents derived from plants of serious mycoses

Antiparasitic agents from natural sources

Artemisinin

Other antimalarial drug candidates from natural sources

Plant-derived antimalarial agents: new leads and efficient

phytomedicines

Cytotoxic and antiplasmodial compounds from the roots of

Strophioblachia fimbricalyx

Antiplasmoidal alkaloids from Cassia siamea

Marine actinomycetes against human malaria

Non-malarial parasitic diseases: leishmania and trypanosomes

Biosurfactants and derivation from natural sources

Potential applications of biosurfactants in medicine

Probiotic bacteria and biosurfactants for nosocomial infection

control

Antimicrobial biosurfactants from marine Bacillus circulans

Pseudomonas aeruginosa rhamnolipids disperse Bordetella

bronchiseptica biofilms

Chapter 6 Lead optimization in infectious disease drug discovery

Summary
Introduction
What is lead optimization?
How is lead optimization conducted?

Lead optimization is a cyclical process

New drugs for old

Lead optimization can make or break drug discovery

The outcome of the lead optimization process

Techniques used in lead optimization
Lead optimization in infectious diseases

In silico tools

Using in silico tools in drug discovery for tuberculosis

Using in silico tools in drug discovery for malaria

Using in silico tools in HIV drug discovery

High content cellular imaging in infectious diseases

Application to bacterial diseases

Toxicogenomics-based assays in infectious diseases

What is the difference between toxicogenetics and toxicogenomics?

Genetic susceptibility factors in infectious diseases

Crystallographic approaches in infectious diseases

Antibiotic drug discovery

HIV drug discovery

Intelligent design in infectious diseases

Partnerships, databases, and networks

The TDR Drug Targets Database

TDR Activities

TDR achievements and goals

The Helminth Drug Initiative

HDI activities

HDI achievements and goals

The Drugs for Neglected Diseases initiative (DNDi)

DNDi achievements to date

Conclusions

Chapter 7 Applications of nanotechnology in infectious diseases

Summary
Introduction
The use of nanotechnology in diagnosis

Quantum dot probes

Synthetic polymers

Nanochips

The use of nanotechnology in novel therapeutics for infectious diseases

Novel delivery methods for antibiotics

Using bacteriophages to deliver drugs

Targeting of bacteriophage systems using polymeric nanostructures

Aerosol delivery systems

Photodynamic therapy systems

Nanoemulsions and nanoparticles

Biofilms

Biofilm infections in cystic fibrosis

Biofilm infections related to catheters

Biofilm infections on prosthetic devices

Novel therapeutic development strategies

Peptide therapeutics

Use of nanotechnology to combat tuberculosis

Use nanotechnology to combat pneumonia

Use of nanotechnology to combat malaria

Use of nanotechnology to combat Sin Nombre hantavirus infection

Using nanotechnology to target fungal infections

Candidiasis

New nanovaccine strategies for infectious diseases

Delivering nanovaccines by injection

Mucosal delivery

Gene vaccines

Novel drug delivery using nanotechnology

Nanotubes

Polyphosphazenes and delivery of vaccine antigens

Solid lipid nanoparticles

Conclusions

Appendix

Bibliography

Chapter 1

Chapter 2

Chapter 3

Chapter 4

Chapter 5

Chapter 6

Chapter 7

Glossary
Index

List of Figures
Figure 2.1: Overview of proteomics
Figure 2.2: Standard proteomic approaches
Figure 2.3: Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) workflow
Figure 2.4: Example of SELDI-TOF workflow
Figure 2.5: Sites of the body usually affected by MSRA infections
Figure 2.6: Pulmonary TB
Figure 2.7: Trichonomas vaginalis in a Pap smear
Figure 3.8: Distribution of proteins produced at different life-cycle stages of Plasmodium falciparum
Figure 3.9: Clostridium difficile colonies on a blood agar plate
Figure 4.10: Structure-activity relationship homology flowchart
Figure 4.11: Novel antiviral strategies based on the HCV life cycle
Figure 4.12: Target identification via pathogen and host genome sequencing
Figure 4.13: Emergence of MRSA in the US
Figure 4.14: Phylogenetic reconstruction based on orthologous glycerol kinase sequences
Figure 4.15: Timeline of antifungal drug development
Figure 6.16: Summary of techniques used in lead optimization
Figure 6.17: Attrition rates and current drug R&D pipeline for neglected diseases
Figure 7.18: Relationship of nanobiotechnology to nanomedicine and other biotechnologies
Figure 7.19: Schematic representation of a drug-carrying bacteriophage
Figure 7.20: Biofilm maturation
Figure 7.21: Single-walled carbon nanotube bundles (SWNT) with adsorbed antibody presentingn that antibody to T-cells

List of Tables
Table 2.1: Advantages and disadvantages of SELDI
Table 2.2: Advantages and disadvantages of MALDI
Table 2.3: Deaths in the UK annually since 1990 from CJD of all known causes