CDD is pleased to host data from phenotypic (whole-organism) screens on the Schistosoma mansoni parasite run at the UCSF Sandler Center for Drug Discovery. CDD now hosts both published [Abdulla et al., 2009] and unpublished screen data on a wide variety of screen collections including those containing compounds already approved for use in humans.
In this guest blog Dr. Conor Caffrey describes his work on the Schistosoma mansoni parasite and invites partners to collaborate in this challenging project.
Schistosomiasis is one of a number of ‘neglected tropical diseases’ (NTDs) associated with extreme poverty. Three species of the Schistosoma flatworm are responsible for most of the infections that occur in sub-Saharan Africa and parts of South America, China and South-East Asia. As many as 700 million people live with the consequences of disease, either through active infection or from permanent tissue damage resulting from previous exposure. Though the disease can be fatal, like other worm diseases, it is better known for long-term disabling infections that are painful, erode quality of life, and degrade societal productivity. Because treatment and control of schistosomiasis relies on just one drug, praziquantel, concern exists over the possible emergence and establishment of drug resistance. In addition, praziquantel has limitations: it does not prevent or decrease re-infection with the parasite and is only effective against the adult stages and not immature parasites. Therefore, it is important to identify alternative therapeutics.
The Sandler Center has invested in the development of a whole-organism screening platform for Schistosoma to allow for more rapid screening of compound collections held at the UCSF Small Molecule Discovery Center and available through third parties. The screen itself remains a work in-progress, but the advances so far have been substantial. We have taken a parasite that requires a lot of maintenance and ‘husbandry’ and married it to our in-house high-throughput robotics systems which had to be re-configured to meet the strict requirements of the parasite. In the 20 years that I have been working with ‘schisto’, this has been a tremendous, hair-pulling challenge, but it has been worthwhile and we continue to learn a lot! We’re now in a position to screen thousands of compounds on a monthly basis and have been fortunate to attract several academic and industrial partners, including from the Bay Area and oversees. We continue to seek collaborative partners for this endeavor.
Manipulating the parasite in an automated manner is one thing, but identifying and quantifying the responses of the parasite to chemicals, is challenging. We’re incorporating high-content screening and image analysis systems that are in place for single-celled organisms and the model worm, C. elegans, but adapting them to the requirements of the schistosome parasite. The parasite displays considerable ‘individuality’ in its basic behavior (the parasite is not clonal) and in response to chemicals. To simplify interpretation, we have been using a constrained nomenclature of text descriptors [Abdulla et al., 2009] to get across the dynamic nature of the parasite’s phenotypic responses to chemicals. For the purposes of identifying compounds that kill, this system works quite well as we can infer dose and time dependencies without the need for expensive imaging technologies. However, for rigorous insight into how the parasite reacts to changes in its environment (beyond ‘just’ drug discovery), the ultimate goal remains to try to capture and quantify all or most of the worm’s response capability. We are making real progress in this area [Singh 2009] but it involves hundreds of hours of ‘data crunching’, machine-time, algorithm development and patience. We have excellent collaborators in Michelle Arkin, Ph.D. (UCSF Small Molecule Discovery Center) and Rahul Singh, Ph.D. (Dept. of Computer Science, San Francisco; who, with their industrial experiences, bring rigor, expertise and an enthusiasm that keeps us moving forward. An NIH-NIAID grant also helps. However, it is also important to recognize the backing of the Sandler Foundation that has provided the consistency to make something as demanding as this work outside of the usual NIH grant cycles and to not lose sight of the fact that new drugs to treat ‘neglected’ worm diseases like schistosomiasis are needed.
Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. Abdulla MH, Ruelas DS, Wolff B, Snedecor J, Lim KC, Xu F, Renslo AR, Williams J, McKerrow JH, Caffrey CR. PLoS Negl Trop Dis. 2009 Jul 14;3(7):e478.
Singh R, Pittas MI, Heskia I, Xu F, McKerrow J, Caffrey CR. Automated Image-Based Phenotypic Screening for High-Throughput Drug Discovery. IEEE Symposium on Computer-Based Medical Systems. 2009.
This blog is authored by members of the CDD Vault community. CDD Vault is a hosted drug discovery informatics platform that securely manages both private and external biological and chemical data. It provides core functionality including chemical registration, structure activity relationship, chemical inventory, and electronic lab notebook capabilities!
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