Shabnam Sigman's blog

Low-Hanging Fruit: An Anti-Parasitic Drug Database

Shabnam Sigman — Tue, 28 Oct 2008 09:30:08 -0700

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which contains ~1,000 compounds, 218 of which are not found in the Microsource or JHCCL collections (P. Phuan, unpublished data).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.

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BSE Case Associated with Prion Protein Gene Mutation

Shabnam Sigman — Wed, 17 Sep 2008 11:08:46 -0700

Last week, co-authors Jürgen Richt and S. Mark Hall published a groundbreaking article in PLoS Pathogens related to mad cow disease. The authors were both affiliated with the US Department of Agriculture during the completion of their study.

Through DNA sequence analysis, the authors identify a novel mutation in the bovine prion protein gene (Prnp), called E211K, in a cow confirmed with atypical bovine spongiform encephalopathy (BSE). This is the first report of a confirmed case of BSE (mad cow disease) with a potential pathogenic mutation within the bovine Prnp gene. This mutation is identical to the E200K pathogenic mutation in the human Prnp, which has been described as the most common cause of genetic Creutzfeldt-Jakob disease.

Richt notes that the mutation can show up at any time, and therefore cattle herders must be on watch. He further recommends that herders try to breed the mutation out of cattle, in order to guard against future BSE-related cases.

About the paper Richt says, “Our BSE manuscript presents critical information on the origin of BSE and will help public and animal health authorities worldwide to design novel prophylactic strategies against this zoonotic pathogen. Your open-access journal is playing a critical role in the dissemination of this information.”

The paper was covered in Reuters and on ScienceBlogs, where the journal is properly attributed, as well as by CBC News and KBS of South Korea, among others.

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On the Origins of Syphilis

Shabnam Sigman — Wed, 23 Jan 2008 16:48:59 -0800

Did Christopher Columbus and his men introduce syphilis into Renaissance Europe, after contracting it during their voyage to the New World? Or does this pathogen have a much older history? A study by Kristin Harper and colleagues published last week in PLoS Neglected Tropical Diseases lends support to what’s known as the Columbian theory of syphilis’s origin while suggesting that the non-sexually-transmitted subspecies arose earlier in the Old World.

The study spread throughout both mainstream press and science blogosphere alike, as did a related Expert Commentary, written by Connie Mulligan and colleagues, that challenged the methods and findings of the syphilis study.

Bora made sure that “syphilis” was the buzzword of the day on ScienceBlogs, and three of his SciBlings’ amazing blogs are highlighted here:

Aetiology: Where did syphilis come from?
Afarensis: Syphils: The View from Bioarchaeology
Greg Laden: The Origin of Syphilis

Jonathan Eisen also blogged about the paper, and drew our attention to a CBC Radio interview with one of the study’s co-authors that you can listen to here.

Carl Zimmer wrote about the paper in Science, and mentions it on his blog.

The study was picked up by more than 100 outlets total. Some of the excellent coverage is highlighted here:

Daily Mail: How Columbus came home with more than he expected
Forbes: Columbus Carried Syphilis From New World to Europe, Study Suggests
Los Angeles Times: Add syphilis to Columbus' discoveries, study says
National Geographic: Did Columbus Bring Syphilis to Europe?
New Scientist: Columbus blamed for spread of syphilis
New York Times: Genetic Study Bolsters Columbus Link to Syphilis
Newsweek: American to Europe: Here, Have Some Syphilis
Reuters: New study blames Columbus for syphilis spread
Scientific American: Did Columbus Bring Syphilis to Europe?
Telegraph: Columbus did bring syphilis from America
Toronto Star: New twist on old scourge
U.S. News & World Report: Columbus Carried Syphilis From New World to Europe, Study Suggests
Wired News: The Real Discovery of Christopher Columbus: Syphilis

The paper was also covered by Economist, Bloomberg, CBC News, CTV.ca, ABC News, MSNBC, Fox News, and, quite unfortunately, Rush Limbaugh.

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PLoS Neglected Tropical Diseases "sneak preview"

Shabnam Sigman — Thu, 30 Aug 2007 09:10:23 -0700

Today PLoS Neglected Tropical Diseases is thrilled to publish its very first set of what we like to call "sneak-preview" articles — articles that are published before the journal officially launches later this year. These two articles showcase the broad-reaching content that will be featured in PLoS' newest journal.

In the Research Article "Genetic Selection of Low Fertile Onchocerca volvulus by Ivermectin Treatment", Roger Prichard and colleagues studied genetic changes in Onchocerca volvulus (the parasite that causes onchocerciasis, or river blindness) following exposure to ivermectin, the primary treatment for onchocerciasis. This new study shows that long-term treatment selects for the heterozygotic form of beta-tubulin, a gene linked to ivermectin resistance.

Then, Sara Lustigman and James McCarter set Prichard et al.’s article in context in their Expert Commentary, "Ivermectin Resistance in Onchocerca volvulus" — Toward a Genetic Basis". These leading experts say that the new study is "a wake-up call for onchocerciasis control programs to select their treatment regimens carefully and to develop plans for detecting ivermectin resistance and the associated genetic markers."

In Prichard and colleagues' study, the genetic changes in beta-tubulin were seen in parasites obtained from patients exposed to repeated ivermectin treatment when compared with parasites obtained from the same patients before any exposure to ivermectin. The researchers also found that the extent of the genetic changes was dependent on the level of ivermectin treatment exposure. Ivermectin has been used for mass treatment of river blindness for up to 18 years and is currently the only safe drug available for mass treatment of the estimated 37 million people infected with O. volvulus.

These two articles are currently available as PDFs; however, once PLoS Neglected Tropical Diseases officially launches, all of its content will feature the interactive online functionality that you've come to expect from its sister journal PLoS ONE. Until then, please post your comments below or contact us directly at plosntds@plos.org.

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Community Meeting to Focus on Diseases of Developing World

Shabnam Sigman — Tue, 27 Feb 2007 15:17:35 -0800

A meeting next week here in San Francisco will feature leading researchers discussing "open" modes of collaborative discovery with a special emphasis on infectious diseases of the developing world.

Collaborative Drug Discovery, Gladstone Center for Translational Research, and the California Institute for Quantitative Biomedical Research (QB3) at the University of California San Francisco (UCSF) will be holding their first Annual Community Meeting on March 5, 12:30-7:00 pm, on the first floor of the Gladstone Institute Auditorium at the UCSF Mission Bay Campus. PLoS will also be in attendance and will be featuring a poster on PLoS Neglected Tropical Diseases.

Confirmed speakers:
* Christopher Lipinski, PhD, Pfizer, retired (Keynote presentation)
* James McKerrow, MD, PhD, Dept. of Pathology, QB3 - UCSF
* Matthew Bogyo, PhD, Dept. of Pathology, Stanford Medical School
* David Roos, PhD, Director Penn Genomics Institute, Univ. of Pennsylvania
* Andrej Sali, PhD, Dept. of Biopharmaceutical Sciences, QB3 - UCSF
* Anang Shelat, PhD, St. Jude Children’s Research Hospital

More about the meeting:
The future role of "open" collaborative drug discovery for research on the infectious diseases of the developing world will be discussed, along with related timely topics. A provocative global research project to speed up malaria drug discovery and the fight against drug resistance by web-sharing unpublished data will be presented. A panel will discuss global health research collaborations from the perspectives of academia, industry, and foundations. In addition to the above-mentioned panel and presentations, the meeting will include 16 posters, software demonstrations, and training for using the CDD Community Database.

If you are in the area, please attend this free meeting, and stop by to meet PLoS staff and learn more about open-access publishing and global health.

Registration is free online. To present a poster, email the poster title and abstract to info@collaborativedrug.com.

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