Strategies to defeat the enemy

Wiesław Swietnicki, Ph.D.

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

Bacteria

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

Customers NATO

Pharma companies – small to medium size

Viruses

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)

Customers NATO

Pharma companies – small to medium size