The following post appeared earlier this week at my Chemical & Engineering News CENtral Science blog, Terra Sigillata. For some odd reason – perhaps this week’s frantic academic schedule of commencement activities – it was not highly read there. I thought that our Science-Based Medicine readers would appreciate it because this new prescription drug is derived from a family of fungi that have been used in traditional Chinese medicine. A few editorial changes have been made later in the post to increase the relevance to our readership here.
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 joint publication of the American Chemical Society and 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 mine 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 blog about 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 [Wednesday] 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.).
Reproduced from Strader et al., J. Nat. Prod. 2011, 74, 900–907.
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 the review:
Isaria sinclairii is native to Asia, mainly China, Korea, and Japan, and is classified as an entomopathogenic fungus. It is the imperfect stage of Cordyceps sinclairii (Clavicipitaceae) and is closely related to Cordyceps sinensis Sacc., whose Chinese name, Dong Chong Xia Cao, means “winter worm, summer grass”; this species was reclassified recently to Ophiocordyceps sinensis. Fungal spores infect the larvae of suitable insect hosts, including members of the order Hymenoptera and Lepidoptera; the fungus is parasitic, growing within the host and resulting in death of the insect. The fungus completely colonizes the insect cadaver, and in the spring and summer white fruiting bodies appear as stalks up to 6 cm in height. Fungi at this stage of development are regarded as mysterious and mystical in some Asian cultures and have been used for thousands of years in traditional Chinese medicine, as they are believed to impart eternal youth.
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 details the reaction schemes and strategies, again pointing out that the two biological assays were crucial to evaluating the structure-activity relationships.
Strader discusses how the molecular mechanism of action of the lead, fingolimod, was then picked up by the group at Novartis, the company that licensed the compound. In this currently-free paywalled article in the “Case Histories” section of Nature Reviews Drug Discovery, Brinkmann et al. detail how fingolimod is actually a prodrug, requiring phosphorylation by sphingosine 2-kinase (SPHK2) to inhibit a series of G-protein-coupled receptors in the sphingosine 1-phosphate (S1P) family. These receptors that bind sphingosine lipids mediate actions of T-cells and endothelial cells that lead to the neuroinflammation of multiple sclerosis.
Most relevant from a drug discovery standpoint is that this mechanism of action is distinct from other immunosuppressants such as FK506 and cyclosporin A which act upstream in this pathway to inhibit serine palmitoyltransferase. This observation is a central theme in natural products pharmacology: naturally-occurring compounds often revealed novel mechanisms of therapeutic action. A far more detailed description of these investigations can be found in this cited review.
Strader then continues in her JNP review to discuss the clinical pharmacology and pharmacokinetics of fingolimod and the other potential uses of the compound, specifically in organ transplantation and cancer therapy. Her review is a lovely example of a comprehensive story that spans from traditional Chinese medicine – where fungi have been used for centuries – to modern drug development.
Why do I single out this review?
As a biologist and pharmacology instructor, I appreciated learning about the chemistry of the drug and the painstaking dissection of its mechanism of action, all directed by a clever battery of bioassays to probe some excellent synthetic work.
Moreover, Strader’s review demonstrates that fungal natural products, while part of our history, remain today a robust source of leads for drug discovery. When studied using solid, science-based techniques, even something as bizarre as an insect fungus can give rise to useful therapeutic agents. In particular, this work demonstrates that drug companies are indeed interested in natural products and can generate new intellectual property and patents: the chemical modifications to ISP-1 created the new composition of matter claim for fingolimod.
Finally, I believe that this published review originated as a graduate class assignment by Cherilyn’s instructor. Ms. Strader seized upon the encouragement of her professor to further develop this story, expanding and refining it to the quality and breadth required to be considered for publication. Cherilyn could have just stopped and gotten an A for the original assignment. Instead, she took on this additional effort under the guidance of my colleagues. She is deserving of congratulations on achieving this milestone. It certainly doesn’t hurt one’s career development prospects to have a review paper among the most highly-read articles in an official journal of the ACS and American Society of Pharmacognosy.
Regular readers know that I am driven to use this blog as a mechanism to recognize the efforts of the next generation of chemists and pharmacologists – students, postdocs, and early-career scientists. As such, please feel free to recommend to me other cases of such publications and interesting backstories that are deserving of this less traditional mode of dissemination.
While this review is currently behind the ACS paywall, many of you should be able to access it via institutional or personal subscriptions.
Reference: Strader, C., Pearce, C., & Oberlies, N. (2011). Fingolimod (FTY720): A Recently Approved Multiple Sclerosis Drug Based on a Fungal Secondary Metabolite Journal of Natural Products, 74 (4), 900-907 DOI: 10.1021/np2000528