Access a complete list of our publications on PubMed
Below is a snapshot of some of the research that we have published under the general research themes for the lab.
Neglected Tropical Diseases and Parasitic Infections
Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery
J. Med. Chem. 2023, 66, 3, 1972–1989
CBL0137(1) is a lead for drug development against human African trypanosomiasis (HAT), a disease caused by Trypanosoma brucei. Through optimization, we were able to increase selectivity vs HepG2 cells and improve solubility. Further optimization is ongoing.
Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis
J. Med. Chem. 2021, 64, 13, 9404–9430
This publication describes the optimization of an azaindole for HAT. Led by graduate student, Dana Klug, we were able to increase solubility and metabolic stability which led to a cure in the acute model of HAT infection. Due to a lack of brain exposure, necessary to treat the chronic form of HAT, we terminated the further optimization of this series. However, this is an excellent example of the research that goes on in the lab, and our ability to drive multiparameter optimization programs.
Improvement of Aqueous Solubility of Lapatinib-Derived Analogues: Identification of a Quinolinimine Lead for Human African Trypanosomiasis Drug Development
J. Med. Chem. 2019, 62, 2, 665–687
Identification of a lead compound that was facilitated by our in-kind collaboration with AstraZeneca, where we are able to drive the optimization of properties, including aqueous solubility.
Anti-amoebic
Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes
Front. Microbiol., Sec. Infectious Agents and Disease, Volume 14 – 2023
We screened ~120 compounds against three pathogenic free-living amoeba, Acanthamoeba castellanii, Naegleria fowleri, and Balamuthia mandrillaris. These compounds were developed in the lab for other indications but largely consisted of kinase inhibitor chemotypes. The preliminary data that we generated yielded compounds with demonstrated efficacy better than the current therapies.
Additional Research Interests
As organic and medicinal chemists, we are well-positioned to be able to contribute to research programs, either from a synthesis perspective or in terms of optimization. Below is a snapshot of some of the research that we have contributed to.
Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2
Nature Communications, volume 14, Article number: 1733 (2023)
Direct-acting anti-virals are of interest since COVID-19, and covalently inhibiting them provides an opportunity to decrease dosing, and the effect of treatment. This work identified a compound with potent inhibition in in vitro target engagement, and whole-cell assays however, it failed to translate to in vivo efficacy. We are currently working to increase oral bioavailability in a program funded by the Stanford AViDD Center.
Functional Characterization of Structural Genomics Proteins in the Crotonase Superfamily
ACS Chem. Biol. 2022, 17, 2, 395–403
The functional characterization of members of the Crotonase superfamily was guided by results from a computational program developed by the Ondrechen lab called Structurally Aligned Local Sites of Activity (SALSA). Our synthetic expertise was required to obtain bicyclo[2.2.2]octane-2,6-dione which was used to successfully characterize, and correct, the function of misannotated proteins.
Commentaries and Reviews
Finding New Collaboration Models for Enabling Neglected Tropical Disease Drug Discovery
PLoS Negl Trop Dis 8(7): e2866
By and large, neglected tropical disease drug discovery happens in academic laboratories and in public–private partnerships—though there has also been a significant and tangible influx of data and research contributions from the for-profit biopharmaceutical industry. Ultimately, it is through collaborative data sharing that we are able to drive drug discovery in a resource-limited environment.
Undergraduate Honors Thesis
Investigation of novel biarylpyrrolidines with activity against Trypanosoma cruzi
Student: Lydia Steger-Wilson, ’24
Chagas disease is a neglected tropical disease caused by the parasite Trypanosoma cruzi. It is estimated to impact over 6 million people across Latin America, particularly people in impoverished areas. The disease progresses through two phases- the acute and chronic phase. The acute phase lasts for 2 months post-infection and patients are generally asymptomatic or have mild symptoms. The chronic phase can persist in an indeterminate form for decades, but 30-40% of patients eventually develop symptoms, including heart failure and gastrointestinal disease. Current treatment options for Chagas disease are limited to two medications, nifurtimox and benznidazole, both of which are only effective for 50-80% of patients when given in the acute phase, and this decreases in chronic Chagas disease. These treatments lack efficacy and can cause side effects like weight loss, nausea, and headaches. This project aims to address the efficacy gap of current treatments by developing a small molecule inhibitor with activity against T. cruzi. A small molecule screen conducted by the Drugs for Neglected Diseases initiative identified a collection of related compounds with activity against T. cruzi, which together form Series 54460. This paper focuses on the optimization of reaction conditions in the pursuit of synthesizing analogs of Series 54460.
Synthesis and Optimization of Inhibitors for Glycogen Synthase Kinase-3β of Trypanosoma cruzi
Student: Tomás Kresina, ’24
American trypanosomiasis, also known as Chagas disease, is a neglected tropical disease caused by the parasite Trypanosoma cruzi (T. cruzi) that affects approximately six million individuals. There are very few effective treatments; those that exist carry harmful side effects, and no new treatments have been approved in the past 50 years. In this project, we utilize structure-based drug discovery and medicinal chemistry to develop novel inhibitors of glycogen synthase kinase-3 beta (GSK-3β) in T. cruzi to improve treatment of infection. The goals of this project are to develop compounds with improved aqueous solubility and selectivity over human kinases while maintaining parasite potency.
Optimization of Biaryl Pyrrolidines: A Potential Hit for Trypanosoma cruzi
Student: Rowan Waring, ’24
Chagas Disease is one of 20 Neglected Tropical Diseases classified by the World Health Organization. It mostly impacts people living in rural areas of South America and is caused by the parasite Trypanosoma cruzi, which is transmitted through the feces of an infected triatomine bug. It infects as many as eight million people in South America and can cause severe symptoms in the determinate chronic stage such as gastrointestinal problems, stroke, and cardiomyopathy. The current treatments available demonstrate low efficacy and can have serious side effects, thus there is need for new medications. However, there is little monetary incentive for companies to invest in drug discovery efforts because the potential to recoup losses is extremely low. Thus, the responsibility for developing new therapies is on the public sector, oftentimes academic institutions. This project focuses on synthesizing analogs of compound series 54460, which originated from a high-throughput screening (HTS) sponsored by the Drugs for Neglected Diseases initiative. These hits were shown to be active against T. cruzi with good host cell selectivity. The synthesis of these analogs was met with several challenges, yet two analogs were synthesized and submitted for biological evaluation.