A guest blog by Michelle Arkin and James McKerrow at The Sandler Center for Research in Parasitic Diseases and the Small Molecule Discovery Center, University of California, San Francisco
Neglected tropical diseases (NTDs) affect hundreds of millions of people worldwide, but are largely ignored by the biopharmaceutical industry because the afflicted are usually poor people in poor regions of the world. As a result, the drug development pipeline for these diseases is largely empty. Furthermore, drugs currently used to treat these diseases may have frequent and severe side effects, efficacy limited to certain stages of the disease, or efficacy only in certain geographical regions. Target-directed drug development for NTDs is one logical approach to fill the pipeline.
A second and very cost-effective approach is “diversity” or “phenotypic” screens where drug libraries are tested directly against parasites in culture without regard to known or validated targets. In one variation of this approach, we searched for previously unrecognized antiparasitics among the drugs currently approved for clinical use. Such hits would be “low-hanging fruit”, with the advantages of proven human safety, and known dosing schedules and pharmacokinetics. Chris Lipinski has estimated there are approximately 2,000 such drugs (www.collaborativedrug.com/register/FDA – register, log in, and go to “data sets”), and an analysis by Chong et al. at Johns Hopkins University puts the number at 3,400 (Chong CR et al. Nat Chem Biol 2: 415-16, 2006). Some of these drugs can be obtained commercially or through material transfer agreements (Microsource, NINDS, Johns Hopkins Clinical Compound Library [JHCCL]). Additionally, Iconix Biosciences has donated to the Sandler Center its proprietary collection, which contains ~1,000 compounds, 218 of which are not found in the Microsource or JHCCL collections (P. Phuan, unpublished data). Close to 30 other companies have donated proprietary libraries to the Sandler Center for screening.
Two years ago, the first screen of the Microsource Spectrum Collection (1,995 compounds) against Trypanosoma brucei was published (Mackey ZB et al. Chem Biol Drug Design 67: 355-63, 2006). Since then, similar screens have been run for Leishmania donovani and Plasmodium falciparum (Weisman JL et al. Chem Biol Drug Des, 2006). The Low-Hanging Fruit site provides a portal by which the community can view hits from these screens and make decisions on which compounds represent the most suitable leads to take to the next step in the drug development pipeline. We have now carried out screens for T. brucei, L. donovani, Entamoeba histolytica, and Schistosoma mansoni using the Spectrum Collection. We are in the process of expanding our dataset using the Iconix library, and we will post this data in the coming months.
The apples on the tree at the website represent links to data for the parasites indicated. In some cases, this data is a simple list of hits to be viewed by those individuals and agencies interested in rapid follow-up. In other instances, a more complete database can be accessed under “protocols and statistics” as compiled by Pipeline Pilot (Accelrys) software.
We view this website as both a resource and a challenge. Through Low-Hanging Fruit, we provide our data on an open-source basis to the antiparasitic drug development community at large. We hope this encourages others to pursue these hits, either as potential drug leads or for target discovery and validation studies. We expect that some of the drug hits will interest researchers with expertise in particular biochemical pathways. We also challenge the community at large to provide their data in a similar open-source manner to encourage new collaborations and follow-up. We envision that this website may serve as one component of a larger community database “hub”, linking global efforts in all stages of the antiparasitic drug development pipeline to initiate new collaborations and minimize redundancy of effort.