Dr. Elizabeth Ponder joined Stanford ChEM-H in 2014 and is currently the Director of Planning and Operations. Dr. Ponder completed her Ph.D. and postdoctoral training at Stanford University in the laboratory of Dr. Matthew Bogyo. Her past work has included promoting public-private partnerships in the non-profit sector, managing multidisciplinary research in the higher education sector, and business development consulting in the for-profit biotech sector. Dr. Ponder joined ChEM-H from the University of California, Berkeley where she served as the Executive Director of the Henry Wheeler Center for Emerging & Neglected Diseases (CEND).
Education & Certifications
Postdoctoral Fellow, Stanford University, Pathology (2010)
PhD, Stanford University, Microbiology & Immunology (2009)
BS, Lafayette College, Biochemistry (2004)
Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery.
PLoS neglected tropical diseases
2015; 9 (6)
Chagas disease is a neglected tropical disease (NTD) caused by the eukaryotic parasite Trypanosoma cruzi. The current clinical and preclinical pipeline for T. cruzi is extremely sparse and lacks drug target diversity.In the present study we developed a computational approach that utilized data from several public whole-cell, phenotypic high throughput screens that have been completed for T. cruzi by the Broad Institute, including a single screen of over 300,000 molecules in the search for chemical probes as part of the NIH Molecular Libraries program. We have also compiled and curated relevant biological and chemical compound screening data including (i) compounds and biological activity data from the literature, (ii) high throughput screening datasets, and (iii) predicted metabolites of T. cruzi metabolic pathways. This information was used to help us identify compounds and their potential targets. We have constructed a Pathway Genome Data Base for T. cruzi. In addition, we have developed Bayesian machine learning models that were used to virtually screen libraries of compounds. Ninety-seven compounds were selected for in vitro testing, and 11 of these were found to have EC50 < 10μM. We progressed five compounds to an in vivo mouse efficacy model of Chagas disease and validated that the machine learning model could identify in vitro active compounds not in the training set, as well as known positive controls. The antimalarial pyronaridine possessed 85.2% efficacy in the acute Chagas mouse model. We have also proposed potential targets (for future verification) for this compound based on structural similarity to known compounds with targets in T. cruzi.We have demonstrated how combining chemoinformatics and bioinformatics for T. cruzi drug discovery can bring interesting in vivo active molecules to light that may have been overlooked. The approach we have taken is broadly applicable to other NTDs.
View details for DOI 10.1371/journal.pntd.0003878
View details for PubMedID 26114876
Validation of the Proteasome as a Therapeutic Target in Plasmodium Using an Epoxyketone Inhibitor with Parasite-Specific Toxicity
CHEMISTRY & BIOLOGY
2012; 19 (12): 1535-1545
The Plasmodium proteasome has been suggested to be a potential antimalarial drug target; however, toxicity of inhibitors has prevented validation of this enzyme in vivo. We report a screen of a library of 670 analogs of the recent US Food and Drug Administration-approved inhibitor, carfilzomib, to identify compounds that selectively kill parasites. We identified one compound, PR3, that has significant parasite killing activity in vitro but dramatically reduced toxicity in host cells. We found that this parasite-specific toxicity is not due to selective targeting of the Plasmodium proteasome over the host proteasome, but instead is due to a lack of activity against one of the human proteasome subunits. Subsequently, we used PR3 to significantly reduce parasite load in Plasmodium berghei infected mice without host toxicity, thus validating the proteasome as a viable antimalarial drug target.
View details for DOI 10.1016/j.chembiol.2012.09.019
View details for PubMedID 23142757
Development of Small Molecule Inhibitors and Probes of Human SUMO Deconjugating Proteases
CHEMISTRY & BIOLOGY
2011; 18 (6): 722-732
Sentrin specific proteases (SENPs) are responsible for activating and deconjugating SUMO (Small Ubiquitin like MOdifier) from target proteins. It remains difficult to study this posttranslational modification due to the lack of reagents that can be used to block the removal of SUMO from substrates. Here, we describe the identification of small molecule SENP inhibitors and active site probes containing aza-epoxide and acyloxymethyl ketone (AOMK) reactive groups. Both classes of compounds are effective inhibitors of hSENPs 1, 2, 5, and 7 while only the AOMKs efficiently inhibit hSENP6. Unlike previous reported peptide vinyl sulfones, these compounds covalently labeled the active site cysteine of multiple recombinantly expressed SENP proteases and the AOMK probe showed selective labeling of these SENPs when added to complex protein mixtures. The AOMK compound therefore represents promising new reagents to study the process of SUMO deconjugation.
View details for DOI 10.1016/j.chembiol.2011.05.008
View details for Web of Science ID 000292583800007
View details for PubMedID 21700208
View details for PubMedCentralID PMC3131534
Functional Characterization of a SUMO Deconjugating Protease of Plasmodium falciparum Using Newly Identified Small Molecule Inhibitors
CHEMISTRY & BIOLOGY
2011; 18 (6): 711-721
Small ubiquitin-related modifier (SUMO) is implicated in the regulation of numerous biological processes including transcription, protein localization, and cell cycle control. Protein modification by SUMO is found in Plasmodium falciparum; however, its role in the regulation of the parasite life cycle is poorly understood. Here we describe functional studies of a SUMO-specific protease (SENP) of P. falciparum, PfSENP1 (PFL1635w). Expression of the catalytic domain of PfSENP1 and biochemical profiling using a positional scanning substrate library demonstrated that this protease has unique cleavage sequence preference relative to the human SENPs. In addition, we describe a class of small molecule inhibitors of this protease. The most potent lead compound inhibited both recombinant PfSENP1 activity and P. falciparum replication in infected human blood. These studies provide valuable new tools for the study of SUMOylation in P. falciparum.
View details for DOI 10.1016/j.chembiol.2011.04.010
View details for Web of Science ID 000292583800006
View details for PubMedID 21700207
View details for PubMedCentralID PMC3131532
Simplified, Enhanced Protein Purification Using an Inducible, Autoprocessing Enzyme Tag
2009; 4 (12)
We introduce a new method for purifying recombinant proteins expressed in bacteria using a highly specific, inducible, self-cleaving protease tag. This tag is comprised of the Vibrio cholerae MARTX toxin cysteine protease domain (CPD), an autoprocessing enzyme that cleaves exclusively after a leucine residue within the target protein-CPD junction. Importantly, V. cholerae CPD is specifically activated by inositol hexakisphosphate (InsP(6)), a eukaryotic-specific small molecule that is absent from the bacterial cytosol. As a result, when His(6)-tagged CPD is fused to the C-terminus of target proteins and expressed in Escherichia coli, the full-length fusion protein can be purified from bacterial lysates using metal ion affinity chromatography. Subsequent addition of InsP(6) to the immobilized fusion protein induces CPD-mediated cleavage at the target protein-CPD junction, releasing untagged target protein into the supernatant. This method condenses affinity chromatography and fusion tag cleavage into a single step, obviating the need for exogenous protease addition to remove the fusion tag(s) and increasing the efficiency of tag separation. Furthermore, in addition to being timesaving, versatile, and inexpensive, our results indicate that the CPD purification system can enhance the expression, integrity, and solubility of intractable proteins from diverse organisms.
View details for DOI 10.1371/journal.pone.0008119
View details for Web of Science ID 000272828800015
View details for PubMedID 19956581
Identification of proteases that regulate erythrocyte rupture by the malaria parasite Plasmodium falciparum
NATURE CHEMICAL BIOLOGY
2008; 4 (3): 203-213
Newly replicated Plasmodium falciparum parasites escape from host erythrocytes through a tightly regulated process that is mediated by multiple classes of proteolytic enzymes. However, the identification of specific proteases has been challenging. We describe here a forward chemical genetic screen using a highly focused library of more than 1,200 covalent serine and cysteine protease inhibitors to identify compounds that block host cell rupture by P. falciparum. Using hits from the library screen, we identified the subtilisin-family serine protease PfSU B1 and the cysteine protease dipeptidyl peptidase 3 (DPAP3) as primary regulators of this process. Inhibition of both DPAP3 and PfSUB1 caused a block in proteolytic processing of the serine repeat antigen (SERA) protein SERA5 that correlated with the observed block in rupture. Furthermore, DPAP3 inhibition reduced the levels of mature PfSUB1. These results suggest that two mechanistically distinct proteases function to regulate processing of downstream substrates required for efficient release of parasites from host red blood cells.
View details for Web of Science ID 000253417400017
View details for PubMedID 18246061
- Ubiquitin-like modifiers and their deconjugating enzymes in medically important parasitic protozoa EUKARYOTIC CELL 2007; 6 (11): 1943-1952