1. Jair L. Siqueira-Neto Assistant Professor
Bringing Hope for the 10 Million People Infected with Life-threatening Kinetoplastid Parasites
Jair L. Siqueira-Neto Assistant Professor

2. Neglected Tropical Diseases
Neglected tropical diseases (NTDs) are a diverse group of diseases that thrive mainly among the poorest populations.
17 NTDs prioritized by WHO affect more than 1.4 billion people:
Let me start talking about Neglected Tropical Diseases
Even though this group of 17 diseases affect 1/5th of the planets population, it is called neglected because the affected population lives in the poverty
Therefore, the pharmaceutical industry has no economical interest to develop therapies for these diseases.
“reading NEGLECTED” in this group of diseases should really make no sense at all!”
They are called neglected because the affected population lives in poverty, so there is no economical interested for a pharmaceutical industry to invest on these diseases.
Thankfully, there is a number of initiatives working to solve the problem of the NTD.
And you will learn about a special one today in three presentations.
In reality, a rash of 17 diseases plague the world's poorest communities
with precisely these problems but these maladies were largely ignored until
three researchers came up with the surprisingly simple idea to "market"
them to politicians and private foundations collectively as "neglected
tropical diseases." The result has been a surge of funding in the last decade.

3. James McKerrow
And I’m also part of the CDIPD, which stands for Center for Discovery and Innovation in Parasitic Diseases.
I’m a faculty member of the Skaggs School of Pharmacy in the beautiful campus of UCSD!
You can see the three words that highlight our mission: “RESEARCH” “EDUCATION” and “AWARENESS”

4. Filling the Innovation Gap
Amebiasis
Naegleriasis
Chagas Disease
Leishmaniasis
Sleeping Sickness
Schistosomiasis
Hookworm
Filariasis
Onchocerciasis
At this Center, we bring top notch science and technology to fill the innovation gap and discover new drugs for the ones in most need. These are the disease models that we currently have,…
(and for each one of these we can have assays and biological systems allowing research from the target selection all the way to a pre-clinical phase – the stage just before testing the drug in humans)
Except for the first two diseases, all the other are part of a group collective called Tropical Neglected Diseases, a term coined by “Peter Hotez”…

5. Collaborations
And I’m also part of the CDIPD, which stands for Center for Discovery and Innovation in Parasitic Diseases.
You can see the three words that highlight our mission: “RESEARCH” “EDUCATION” and “AWARENESS”

6. Technology

7. Compound Management Room
Screening Platform
Screening Laboratory
Snail Farm
Compound Management Room
Storage Room
Tissue Culture Rooms

8. Screening Platform ImageXpress Micro Biomek FX Robotic Arm Envision
ATS

9. Disease Models

10. Neglected Diseases caused by Kinetoplastid Parasites
Sleeping Sickness
Leishmaniasis
Chagas Disease

11. Trypanosoma cruzi life cycle
Rassi et al, Lancet 2010

12. T. cruzi high-content screening assay
Myocyte
T. cruzi
6-8 days
T. cruzi (Trypomastigote)
Plate containing
compounds
C2C12 cells
3 days
infect
Fixing & Staining
Reading

13. Image Analysis
Moon et al, Plos One, 2014

14. Image analysis for efficacy assessment
NUMBERS
IMAGES

15. Primary Screening Normalized Activity (%) Number of host cells
Benznidazole
“Hits”
Tested compounds
Number of host cells
0.1% DMSO

16. Screening Natural Products

17. Screening of Natural Products
6,000 selected pre-fractions
x 20 cpds/pre-fraction
120,000 individual cpds
Unspecific toxicity filter
3,020 selected pre-fractions
Anti-parasitic screening
102 pre-fraction hits
Peak-libraries
33 hit cpds

18. Pure Compounds EC50 CC50 Max. Activity RLUS2214E3B 0.04 uM >20 uM
DMSO
EC50
CC50
Max. Activity
RLUS2214E3B
0.04 uM
>20 uM
90%
RLUS2214E1
1.3 uM
70%
RLUS2214E3C
8 uM
65%
RLUS2214E5
10 uM
60%
RLUS2214E3D
>10 uM
RLUS1849C1B
Phenotype
0.08 uM
2.5 uM
10 uM
10 uM
10 uM
10 uM

19. Public-Private Partnership

20. University of California & GNF Novartis
Chagas Disease Drug Discovery & Development
Neitz et al, J. Biomolecular Screening, 2015

21. In silico tools to optimize drug discovery

22. Bayesian Machine Learning Models
Selleck Chemicals natural product lib. (139 molecules);
GSK kinase library (367 molecules);
Malaria box (400 molecules);
Microsource Spectrum (2320 molecules);
CDD FDA drugs (2690 molecules);
Prestwick Chemical library (1280 molecules);
Traditional Chinese Medicine components (373 molecules)
The models were all generated using the following molecular descriptors: molecular function class fingerprints of maximum diameter 6 (FCFP_6) [78], AlogP, molecular weight, number of rotatable bonds, number of rings, number of aromatic rings, number of hydrogen bond acceptors, number of hydrogen bond donors, and molecular fractional polar surface area which were all calculated from input sdf files.
7569 molecules
99 molecules
Ekins et al, PLoS NTD, 2015

23. HIT CONFIRMATION (dose-response)
Comparing Diversity Screening vs Optimized
99 molecules
SCREENING
HIT SELECTION
HIT CONFIRMATION (dose-response)
SUITABLE FOR IN VIVO
In Vivo Efficacy
Ekins et al, PLoS NTD, 2015

24. Pyronaridine 85% efficacy Ekins et al, PLoS NTD, 2015 Infection
Infection
Treatment
Reading
85% efficacy
Ekins et al, PLoS NTD, 2015

25. Pyronaridine: anti-Chagas candidate and Known anti-Malaria
Grant for scaffold development & target ID

26. Ciencia na Escola
Startup
Entrepreneurship
Education and Social Impact

27. Knowledge is like a garden
if it is not cultivated it cannot be harvested
African proverb
Funding acknowledgments
So let’s all water fertilize this garden together.