global health, neglected diseases, and drug development -- a newcomer's perspective
DESCRIPTION
Greg Crowther's talk to Glacier Peak High School's "Biotechnology and Global Health" class.TRANSCRIPT
Global health, neglected diseases, and drug development – a newcomer’s perspective
early-stageresearch
preclinicalstudies
clinicaltrials (I)
clinicaltrials (II)
clinicaltrials (III)
FDA review& approval
market
Gregory J. Crowther, Ph.D.
Department of Medicine
University of Washington
http://faculty.washington.edu/crowther/
What does that title mean?
• “Global health” …
• “Neglected diseases” …
• “Drug development” …
about health disparities between rich & poor
malaria, tuberculosis, dengue, filariasis, etc.
early-stageresearch
preclinicalstudies
clinicaltrials (I)
clinicaltrials (II)
clinicaltrials (III)
FDA review& approval
market
“A shot at adulthood” video
http://zooppa.com/ads/uw-pocket-media-film-festival/videos/a-shot-at-adulthood
Drug development for neglected diseases:Why is it so hard?
• Drug development in general is hard!
• Limited financial incentives for companies– cost of discovery/development– cost of manufacturing/distribution
• Limited knowledge/interest among rich nations– apathy of general public– limited scientific resources, need for big teams
• Implementation across continents and cultures– e.g., nonuniform drug production/use
• Nonhuman hosts for diseases – e.g., insects, pets
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• Philanthropy– charities (e.g., Gates Foundation)– corporations (e.g., GlaxoSmithKline, Novartis)
• Communication– raise awareness in wealthy areas (e.g., USA)– coordinate with people in disease-prone areas– share data, coordinate research teams
• Technology– informatics (analyze huge datasets with computers) – high-throughput screens (quickly test many samples)– structure-based drug design (study proteins in 3D)
Drug development for neglected diseases:Are there reasons for optimism?
What would a perfect drug be like?
• effective (eliminates infection completely)• brief treatment regimen• safe (doesn’t harm humans)• delivered orally • cheap to make and distribute• how it works is clear (specific target)• “resistance to resistance”
What would a perfect drug be like?
• effective (eliminates infection completely)• brief treatment regimen• safe (doesn’t harm human cells)• delivered orally• cheap to make and distribute• how it works is clear (specific target)• “resistance to resistance”
Informatics- pick pathogen proteins to disrupt with drugs- predict how chemicals will behave in body
What would a perfect drug be like?
• effective (eliminates infection completely)• brief treatment regimen• safe (doesn’t harm humans)• delivered orally• cheap to make and distribute• how it works is clear (specific target)• “resistance to resistance”
High-throughput screens- test lots of chemicals simultaneously - test compounds against proteins and/or cells
Image: alphahelix.co.uk
What would a perfect drug be like?
• effective (eliminates infection completely)• brief treatment regimen• safe (doesn’t harm humans)• delivered orally• cheap to make and distribute• how it works is clear (specific target)• “resistance to resistance”
Structure-based drug design
Nelfinavir in the active site of HIV-1 protease. Image from C.M. Henry, C&EN 79:
69, 2001.
Recent advances in malaria research:cool example #1
• GlaxoSmithKline (Spain)– screened ~2,000,000 chemicals for
ability to kill parasite cells!– found ~14,000 hits!– 82% of hits “originate from internal
company projects and are new to the malaria community”
– structures of all hits are shared in public databases Reference:
F.J. Gamo et al., Nature 465: 305, 2010
Recent advances in malaria drug research:cool example #2
• Novartis (San Diego and Singapore)– screening hits were modified chemically and tested– potent inhibitor of parasite growth was identified– how does the inhibitor work? (what is its target?)
• parasite evolved resistance to inhibitor• genomes of resistant parasites were sequenced• mutations consistently occurred in one specific membrane
protein (transporter)
Reference: M. Rottmann et al.,
Science 329: 1175, 2010
Conclusion
• Gates Foundation’s motto: “All lives have equal value”
• New technologies (e.g., informatics, high-throughput screens, structure-based drug design) will help us develop new drugs for neglected diseases
• Lots of ways to get involved– educate yourself
– talk (blog, IM, text, tweet) with others
– raise money
– consider career options
T I M E S’ U P
The malaria song
MalariaI just had a chill from malariaAnd suddenly I knewA fever would come tooAnd sweat…
MalariaI think I will die from malariaMy breathing labors onMy consciousness is goneI’m pale…
MalariaSing it soft and you’ll hear skeeters whiningSing it loud and your spleen will be piningMalaria, Malaria, Malaria, Malaria
to the tune of “Maria” (West Side Story)
music by Leonard Bernstein
lyrics by Wes Van Voorhis, MD, PhD
Recent advances in malaria research:bonus example
• Pradip Rathod (UW) and Meg Phillips (Texas)– parasite DHODH should be a good drug target (involved in
synthesis of pyrimidines for nucleic acids)– high-throughput screen found good inhibitors of parasite
DHODH that don’t inhibit human DHODH
– these inhibitors didn’t cure malaria in mice, but more derivatives were made, and some work!
Reference: R. Gujjar et al., Journal of Medicinal Chemistry 52: 1864, 2009.
Research frontier: the challenge of drug resistance and “polypharmacology”
• Some drugs don’t target a single protein• Drug resistance should be less of a problem
for multi-protein inhibitors (Why?)• How to find new multi-protein inhibitors?
– inhibition of several related proteins?– inhibition of disparate proteins?
Image from Chemical & Engineering News after M.J. Keiser et al., Nature 2009