Fingolimod (Gilenya; Novartis) for Multiple Sclerosis
May11

Fingolimod (Gilenya; Novartis) for Multiple Sclerosis

A very well-written review of an orally-active drug for multiple sclerosis has just appeared in the April 25th issue of the Journal of Natural Products, a publication of ACS in conjunction with the American Society of Pharmacognosy. The review, Fingolimod (FTY720): A Recently Approved Multiple Sclerosis Drug Based on a Fungal Secondary Metabolite, is co-authored by Cherilyn R. Strader, Cedric J. Pearce, and Nicholas H. Oberlies. In the interest of full disclosure, the latter two gentlemen are research collaborators of ours from Mycosynthetix, Inc. (Hillsborough, NC) and the University of North Carolina at Greensboro. My esteemed colleague and senior author, Dr. Oberlies, modestly deflected my request to post here on the publication of this review. So, I am instead writing this post to promote the excellent work of his student and first author, Cherilyn Strader. As of this morning, this review article is first on the list of most-read articles in the Journal. This status is noteworthy because the review has moved ahead of even the famed David Newman and Gordon Cragg review of natural product-sourced drugs of the last 25 years, the JNP equivalent of Pink Floyd’s The Dark Side of the Moon (the album known for its record 14-year stay on the Billboard music charts.). The story of fingolimod is a fascinating journey from early 1970s work on fungal-derived immunosuppressants in Japan to synthetic organic synthesis by Tetsuro Fujita at Kyoto University in 1992 that has led to a non-injectable option for patients with multiple sclerosis. Some of these fungi are ones that infect insects and their fruiting bodies have been used in traditional Chinese medicine as elixirs. From a biology standpoint, Ms. Strader very nicely describes the in vitro and in vivo assays used to identify the natural product progenitor from Isaria sinclairii, myriocin (ISP-1), as an immunosuppressant agent. A clever mixed lymphocyte assay was used by Fujita and colleagues to detect inhibition of T-cell proliferation when splenocytes from two strains of mice were co-cultured in the presence of alloantigen. To confirm activity in vivo, the investigators then used rat skin transplant model where tissue would normally be rejected when transplanted from one rat strain to another. Active compounds were scored based on their ability to prolong the viability of the transplant. This work from the Journal of Antibiotics is available here as free full text. In both the in vitro and in vivo assays, ISP-1 exhibited activity superior to that of the immunosuppressant, cyclosporin A. But as with many natural products, the compound has some toxicity and solubility issues. Several groups went on to synthesize over 50 analogs of the ISP compounds and Ms. Strader...

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Graduate training: Choosing a n00b vs. a greybeard
May04

Graduate training: Choosing a n00b vs. a greybeard

I hope that you have been to BenchFly, the brainchild of Dr. Alan Marnett, third-generation chemist and chemical biologist. Founded in Cambridge, MA, in 2009, Benchfly is a highly-functional and beautifully-designed site for the practicing scientist, directed primarily toward those developing their scientific chops (and for more, uh, senior folks looking for a methods tune-up). Based around a core of open-access instructional video protocols on techniques from how to prepare a sample for NMR to siRNA transfection to how to unlock a jammed Beckman J2-21 centrifuge, BenchFly also addresses cultural aspects of the scientific life with the input of a growing community of interdisciplinary scientists that range from undergraduates to department chairs. Chemists will fully appreciate the video on how to pronounce “Hoechst” after hearing it mangled by American biologists who use the company’s fluorescent intercalating DNA dyes (solution: ask a German scientist!). And at the conclusion of their nicely-crafted mission and values statement comes this: “We believe the only thing more powerful than Chemistry is Chuck Norris. Period.” BenchFly also has had contests for best design of a flavors.me personal lab landing page and routinely catalyzes career discussions through their blog. On Monday, Alan put up a post asking a crucial question of relevance to the first-year graduate student: If you were picking a lab, would you be more or less likely to work for an assistant professor (eg, non-tenured)? The post ends with that as a survey question but Alan’s analogy to a racetrack outing with his old lab nicely frames the question. The discussion there has been fairly balanced and the survey results are currently running with a slight 52-48 percent edge for the benefits of working with an assistant professor over a tenured full professor (apologies to my women colleagues for use of the term “greybeard” but I use it pejoratively to reflect my dismay at the current paucity of women in senior scientific positions). I picked a n00b I can offer my own perspective at 25 years out from choosing a freshly-minted assistant professor who wasn’t even at my graduate institution when I came to interview. My mentor, Tom Rowe, came to the Department of Pharmacology and Therapeutics at the University of Florida from a postdoc with Leroy Liu at Johns Hopkins. There, he worked to identify type II DNA topoisomerases as the target of anticancer drugs like doxorubicin (Adriamycin), the epipodphyllotoxins etoposide and teniposide, and the experimental aminoacridines. It was in Tom’s lab was where I first gained my molecular biology skills while also bearing witness to The Awesome Power of Natural Products. I’ve been playing phone-tag with Tom over the last couple of...

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