Comparative Genomics and Proteomics in Drug Discovery: Vol 58

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ISBN: 9780415396530 | 0415396530
Cover: Nonspecific Binding
Copyright: 12/13/2006

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Comparative Genomics and Proteomics in Drug Discoverygives an overview of how emerging genomic and proteomic technologies are making significant contributions to global drug discovery programs, and in particular the key role that comparative genomics and proteomics play within this strategy. Each chapter is written by respected authorities, with hands-on experience, from both academic and pharmaceutical backgrounds.

Contributors	p. ix
Preface	p. xi
Comparative genomics and drug discovery in trypanosomatids	p. 1
Introduction	p. 1
General characteristics of trypanosomatids	p. 1
Life cycles	p. 3
Pathogenesis	p. 5
The genomes of trypanosomatids	p. 6
Karyotype and genome organization	p. 6
Chromosome polymorphism: subtelomeric regions	p. 9
Sequenced genomes	p. 10
Comparative genomics of trypanosomatids	p. 11
Synteny in trypanosomatids	p. 11
Possible hypothesis for explaining synteny	p. 12
Synteny breaks: retrotransposon-like elements and subtelomeric regions	p. 13
Species-specific genes and domains	p. 14
Drug Discovery in trypanosomatids	p. 15
Introduction	p. 15
Strategies	p. 17
References	p. 19
The practical implications of comparative kinetoplastid genomics	p. 25
Introduction	p. 25
The diseases	p. 26
Current treatment	p. 27
The moral issue	p. 28
The Tritryp genome projects	p. 29
Tritryp genome architecture	p. 32
Core proteome	p. 34
Species specificity	p. 35
Metabolism	p. 35
Beyond sequencing	p. 38
Protein structure and crystallisation	p. 38
Elucidating parasite pathways	p. 39
Whole genome microarrays	p. 39
Two-dimensional gel/mass spectrophotometry studies	p. 39
Vaccine studies	p. 40
Drug target portfolios	p. 40
Gene knockout and knockdown	p. 40
Annotating and assembling related genomes	p. 41
Future comparative sequencing projects	p. 41
References	p. 43
The relevance of host genes in malaria	p. 47
Introduction	p. 47
The pre-erythrocytic stage: hepatocyte, liver and beyond	p. 47
The erythrocytic stage and disease	p. 49
Erythrocyte invasion - P. vivax versus P. falciparum	p. 50
Intraerythrocytic stage - globin and non-globin genes	p. 51
Cytoadherence and sequestration - selective pressures and therapeutic value	p. 54
Host's immune response	p. 59
Final remarks: exploring the host potential in the 'post-omics era'	p. 66
References	p. 67
Nicotinic acetylcholine receptors as drug/chemical targets, contributions from comparative genomics, forward and reverse genetics	p. 93
Introduction: nicotinic receptor structure and function	p. 93
Nicotinic receptors: roles in human disease	p. 94
Epilepsy	p. 94
Congenital myasthenias	p. 95
Myasthenia gravis	p. 95
Rasmussen's encephalitis	p. 95
Nicotinic receptors as drug/chemical targets	p. 95
Human drug targets	p. 95
Control of nematode parasites and insect pests	p. 96
Comparative genomics of nAChR families and their contribution to understanding drug selectivity	p. 97
Mammals	p. 97
Other vertebrates	p. 97
Invertebrate model organisms: the nematode, Caenorhabditis elegans, and the fruitfly, Drosophila melanogaster	p. 98
Vectors, pests and beneficial insects	p. 98
Splicing and RNA editing in nicotinic acetylcholine receptors adds to diversity	p. 99
Forward genetics in the study of C. elegans nicotinic receptor subunit function	p. 102
Reverse genetics in the functional analysis of nicotinic acetylcholine receptors	p. 103
Heterologous expression studies on nAChRs provide insights into selectivity of neonicotinoids for insects over vertebrates	p. 104
Conclusions: lessons from comparative genomics of nicotinic acetylcholine receptor families	p. 105
References	p. 105
Discovery of novel sodium channel inhibitors: a gene family-based approach	p. 115
Introduction to voltage-gated sodium channels	p. 115
Sodium channels and inherited diseases	p. 116
Sodium channel blocking drugs	p. 118
A gene family-based approach to Na[subscript v] channels	p. 122
Distribution studies of human Na[subscript v] subtypes	p. 122
Functional studies of human Na[subscript v] subtypes	p. 123
Pharmacological studies of the human Na[subscript v] subtypes	p. 128
Summary and future prospects	p. 129
References	p. 130
'Omics' in translational medicine: are they lost in translation?	p. 133
Introduction	p. 133
'Omic' technologies: a capsule	p. 134
Defining translational research/medicine	p. 134
Are 'omics'-derived markers being 'Lost in Translation'?	p. 135
Is it a question of getting the biology straight?	p. 136
What are the factors contributing to the inability to rapidly move the products of omic platforms towards standardized, reproducible, clinical diagnostic tools?	p. 137
Are the paradigms shifting?	p. 139
Going rapidly forward	p. 141
References	p. 142
Drug-target discovery in silico: using the web to identify novel molecular targets for drug action	p. 145
Introduction	p. 145
Defining and identifying drug targets	p. 146
Sequence databases	p. 151
Sequence databases for endogenous diseases	p. 152
Sequence databases for exogenous diseases	p. 154
Automated genome annotation tools	p. 157
Text-mining tools	p. 159
Integrated drug/sequence databases	p. 162
Analytical tools for drug-target discovery	p. 166
Conclusion	p. 170
References	p. 172
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Comparative Genomics and Proteomics in Drug Discovery: Vol 58

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