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BackgroundSolutions Problems
Therapeutics-antibiotics
Bacteria
Vaccines
Bacteria and viruses
Antibiotic resistance
Specificity/side effects
Possibility of genetically-engineered resistance
Recombinant- time to design, limited antigen repertoire
Live- faster, side effects
Therapeutic strategiesSolutions Pros/Cons
Metabolic network
Bacteria mostly
Virulence systems
Bacteria
Conserved – universal target, longer to develop resistance
Takes time to starve bacteria
Independent of antibiotics/vaccines – can defeatgenetically-engineered species
Host kills the pathogen
Cannot reverse effects of secreted toxic proteins
VaccinesSolutions Pros/Cons
Recombinant
Natural/live
Defined antigen target Intra- and extracellular
pathogens Low cost Limited antigen variability Time to develop immunity
Broad antigen repertoire Low cost VERY effective Side effects Time to develop immunity
Metabolic network Easy to build a model and analyze
Targets easily identified and structures known/modelsbuilt
Selective for bacteria
Strategy- block active site
Rational design – tools developed
Resistance- after along time
Requires low capital to design drugs – Poland?
Potential targets Class A, B and C Select Agents
Regular pathogens
Examples: amino acid biosynthesis, fatty acidbiosynthesis, nutrient procurement
Drugs- small molecules
Metabolic networks Genome sequenced- 1-2 days now
Targets identified- genome analysis (MetaCyc)- 1 day
Model constructed -1 day
Computational screen – 1 day
In vitro testing-1 month
Analogs search and screen– 1 month
Optimization- cell culture - 3-6 months
Final test in a cell culture – 1 month
nM and below- X-ray data for co-crystals – 1 year
Virulence systems-rational Genome sequenced- 1-2 days
Targets identified- systems biology analysis - 1 day
Model constructed -1 day
Computational screen – 1 day
In vitro testing-1 month
Analogs search and screen– 1 month
Optimization- cell culture - 3-6 months
Final test in a cell culture – 1 month
nM and below- X-ray data for co-crystals – 1 year
Phenotypic screens HTS assay design 1-3 months
2000K screen -1-2 weeks
50 selected
Analogs search and screen– 1 month
Optimization- cell culture - 3-6 months
Final test in cell culture – 1 month
nM and below- extensive chemistry/QSAR– 1-2 years
Off-targets search – 1 year or more
Live vaccines Genome sequencing 2-3 days Target identification 1 -3 days
Cell entryProtein processingMetabolismViral assemblyStructural proteins
Genetic engineering 3 monthsReconstruction - synthetic biologyEpitope grafting – safe viruses, bacteria
Animal validation 8 months(6 months protocol + 2 months experiments)
Recombinant vaccines Targets validated 8 months
Single/multiple proteins tested 8 months
VLPs
Capsid assembly system testing 3 months
Animal testing 8 months
Small molecules Cell entry – membrane fusion
Protein processing- viral proteases
Metabolism – viral enzymes
Viral assembly – structural proteins
Each strategy requires
- 3+ years to optimize
- an HTS screening system (computational or
experimental)
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