1. Pharmaceutical Approaches to Antiviral Drug Discovery
Peter S. Dragovich
Pfizer Global Research and Development
La Jolla Laboratories

2. Exploratory Development
Drug Discovery/Development Pipeline
Multifaceted, complicated, lengthy process
Today's Focus
Pharmacology
Pre-clinical
Clinical Pharmacology
& Safety
Pre-clinical Safety
Products
Discovery
Exploratory Development
Full Development
Phase I
Phase II
Phase III 5 10 15
Idea
Years
Drug

3. Drug Discovery Pipeline
Multifaceted, complicated, lengthy process
Up to 5 years to complete development transition
Start
3-5 years
Product Profiles
Clinical
Commercial
TA Lead.
Target Identification
Virology
Cell Biol.
Lead generation
Mol. Biol.
Biochem.
HT Screening
HT Chem.
Comp. Chem. Crystallog.
Lead optimization
Med. Chem.
Res. Pharm.
PDM
Safety
Process Chem.
Dev.

4. Patient/Product Profiles
Identify areas of high unmet medical need
Sub-optimal or no existing therapies
10.0
Concentration (g/ml)
0.01
0.1
1.0
Identify differentiation basis for new therapy
potency/efficacy
resistance profile
dose size/frequency
safety/tolerability
Lab objectives which address desired profiles

5. Drug Discovery Pipeline
Start
0.5-1 year
Target Identification
Product Profiles
Lead generation
Lead optimization
Dev.
Biological entity associated with disease of interest (host or virus origin)
Appropriate modulation of target anticipated to impact disease in manner consistent with product profile

6. Target Identification
Analyze virus life cycle
Identify critical points for intervention (host or virus origin)
Host Cell
Nucleus
1. Entry
2. Replication
4. Release
3. Assembly

7. Target Identification Criteria
Activity/function essential for viral replication
Proven or inferred through biological experimentation
Drugable target (subjective!)
Known small molecule inhibitors
Well defined active (binding) site
Historical success against related targets
Conservation across virus variants (where applicable)
Selectivity vs human proteins
Difficult to incorporate all criteria in single target

8. Ki <1 nM (human renin)
Target Identification
Example: HIV Protease
Importance inferred from biology; proven through experimentation1,2
Pr5160 gag-pol 1 2 3 4
Pr55 gag
p17
p24 p1 p9 p6 TF PR RT RN IN 5 6 7 8
Ki <1 nM (human renin)
Aspartyl protease
Potent renin inhibitor examples
Large, lipophilic molecules
1. Kohl, N. E.; et al. Proc. Natl. Acad. Sci. USA 1988, 85, 4686.
2. Kramer, R. A.; et al. Science 1986, 231, 1580.

9. Drug Discovery Pipeline
Start
0.5-1 year
Product Profiles
Target Identification
Lead generation
Lead optimization
Dev.
Identify molecule(s) which interact with chosen target
Biological properties attractive/promising but not ideal
Amenable to analog production

10. Lead Generation Need reliable and accurate biological assays
Routine production of target protein
Primary biochemical assay
Primary antiviral assay
Secondary assays (counterscreens)

11. Deoxythymine substrate
Lead Generation
Substrate/Ligand analogs
Biology or target mechanism must be known
Example: HIV RT nucleoside inhibitors
DNA/RNA template
Deoxythymine substrate
Synthesized DNA
AZT
Incorporated into viral DNA by RT enzyme
Terminates synthesis (lacks 3'-hydroxyl)
AZT

12. Lead Generation High-throughput screening
Large chemical archives (500K to 2MM compounds)
Miniaturization = improved cost-effectiveness

13. Lead Generation High-throughput screening
Allows for chance discovery of novel inhibitors
Example: HIV RT non-nucleoside inhibitors
Bind to allosteric site on enzyme surface
Disrupt enzyme structure/function
Efavirenz

14. Drug Discovery Pipeline
Start
2-3 years
Product Profiles
Target Identification
Lead generation
Lead optimization
Dev.
Prepare/synthesize analogs of leads
Improve biological properties
Optimized compound(s) suitable for clinical development

15. Typical project progression
Lead Optimization
Iterative process impacted by technology
Combinatorial
Chemistry
Structure-based
design
Idea Generation
Chemical Synthesis
Data Analysis
Computational
evaluation
Biological Evaluation
Biochemical assays
Antiviral assays
Met./abs./sol. assays
Pharmacokinetics
in vitro / in vivo
Safety assessments
Development
Candidate
Typical project progression

16. Future AV Discovery Needs
Continued understanding of patient and physician needs
Product Profiles
Target Identification
Lead generation
Lead optimization
Start
Dev

17. Future AV Discovery Needs
Good understanding of patient and physician needs
Better understanding of virus biology
New target opportunities
Rapid identification of new viral diseases (SARS)
Improved association of viral infection with existing diseases
Target Identification
Product Profiles
Lead generation
Lead optimization
Start
Dev

18. Exploratory Development
Future AV Discovery Needs
Improvements in drug discovery/development processes
Shorten timelines
Reduce attrition
Lead optimization cycle times
Safety predictions
Clinical development times
Products
Discovery
Exploratory Development
Full Development
Phase I
Phase II
Phase III 5 10 15
Idea
Years
Drug

19. Target Identification
Summary
Antiviral drug discovery
Multifaceted, complicated, lengthy process
Application will lead to future antiviral therapies which address areas of high unmet medical need
Start
3-5 years
Product Profiles
Target Identification
Lead generation
Lead optimization
Dev.

20. Acknowledgements Marc Deller Jay Davies Amy Patick Rich Michitsch
Larry Truesdale