Microcystins – leads for anticancer drugs

In one of my first blog posts I have shortly discussed that the hepatotoxic microcystins, cyclic peptides from cyanobacteria, are currently studied for their potential as leads for anticancer drugs. I also mentioned a poster we presented at the ICNPR 2012 in New York.

Recently, the paper covering our work in this field has been published in PLOS ONE. It describes the cytotoxic potency and the OATP1B1/1B3 transporter selectivity of 23 naturally occurring microcystin congeners. Microcystin variants with cytotoxic OATP1B1/OATP1B3 IC50 ratios that ranged between 0.2 and 32 were found, representing a 150-fold range in transporter selectivity. We found that microcystin structure has a significant impact on transporter selectivity, and thus it should potentially be possible to develop analogs with even more pronounced OATP1B3 selectivity and thus enable their development as anticancer drugs (some cancer types express OATP1B3 and could thus be targeted; for more information see the paper…).

For the figure depicting the chemical structure of microcystins / nodularins I have compiled a list of all congeners described in the literature to date. The data are available at figshare. If you are interested in microcystins you should definitely take a look at this list.

Interestingly, some weeks ago I met a synthetic chemist at a conference who works on a microcystin synthesis, and we started talking about a collaboration. This will be a great opportunity to further explore the chemical space around the microcystins, hopefully leading to derivatives with higher selectivity, potency and better pharmacokinetic properties…

New position / Blog hiatus is over (hopefully…)

Wow, is it really more than half a year since my last post? So much has happened in this time…

The reason for this long silence has been that I have been absolutely busy. I did really like my position as Head of Natural Product R&D at Cyano Biotech, but when I saw the open position for an Assistant Professor for antiinfective natural product research at the University of Tuebingen in May last year, I could not resist but applied for this position. Already in June I had the opportunity to present myself, and I had a lot of work preparing the presentation I gave and also preparing for the talks afterwards. Already in August I received word that the comission has chosen me for the position, and they wanted me to start as soon as possible – which in the end was November. In these few months I had to arrange everything at my old job, had to organize new equipment for the lab in Tuebingen, had to write a first grant application (deadline was even before I took up work at university…), had to find a place to live in, and so on. No time to blog…

Now I have settled down a bit (still have to write some additional grant applications with close deadlines, though…) and will resume blogging now and then, although there is still a lot of work – but I really do enjoy my new tasks.

My new position is part of the German Centre for Infection Research (DZIF), and from now on I will focus on antiinfective natural products. From my predecessors I have “inherited” a well equipped natural product chemistry lab, a nice actinomycete strain collection, and a library of about 400 natural products mainly isolated from actinomycetes. To this I will add my expertise with cyanobacteria and fungi, making it a nice mix of organisms to be studied. Let us see what we can do to battle multiresistant bacteria, evil viruses, and neglected infectous deseases… ;-)

My latest paper and why I am somewhat proud of it

These days my latest paper has been published.

To say it most frankly: This is not big science. The paper reports the isolation and structure elucidation of two compounds from a fungus, and neither is the core structure of these compounds novel nor do they have some remarkable bioactivity. It will be only interesting for a few scientists working in the field, and nobody would have missed the results had I not published them.

But still – I am somewhat proud of this paper for three reasons:

  • I have published this work in an Open Access journal dedicated to Natural Product Research (I have discussed this journal before). I am both a Natural Product and an Open Access freak, so the combination of these two fields is brilliant.
  • The data for this publication comes from my time as a PhD student – they slept on my hard disc for nine long years. No data deserve to be in prison for so long, so I just needed to set them free!
  • I have deposited the complete MS and NMR data in an open repository (figshare), so that everyone interested can download the data and have a look at the raw NMR spectra.

Especially the last point is most important for me. How often have I been frustrated because the NMR spectra shown in the Supporting Information have been only of little help, printed on one page as they are? And to come back to this recent paper: I contacted the authors of a paper discussing similar compounds and asked them for a spectrum to compare with my own spectrum – and the answer I received was “Actually it is a great honor for us to attract your attention in our work. Actually me, as i am the first author of the article, i did not find the charts as i am no longer in Japan now, that paper was during my PhD in Japan, now i returned back home but unfortunatelly i could not find it with my documents here.” What kind of science scrutiny is this?! Had they uploaded their data somewhere…

We have arrived in 2013 – it is absolutely no problem to deposit hundreds of MB of raw data “in the cloud” where anybody interested can download the data free of charge and play with them. I sincerely wish this would become the standard in Natural Product Research, where correct interpretation of e.g. NMR data as well as comparison of data to facilitate structure elucidation are so important.

Funnily enough, the publisher, Springer, makes mentioning this in the manuscript harder than necessary. It has not been possible to write the sentence “Complete NMR raw data are available for download at…” in the Supporting Information paragraph at the end of the paper, as this paragraph cannot be modified by the authors. How strange – the ACS allows writing there freely – why does Springer not? Furthermore, the paragraph dictated by Springer contains the phrase “[Supplementary material] is accessible for authorized users”. How much sense does this make for an Open Access journal? And what kind of access rights does one need to download a Supporting Information file? This kind of stuff has never been behind any pay wall with any publisher (at least as far as I know…).

However, my two main messages for today:

Do not imprison your research data!

Do not only publish open access – also publish your raw data!

Natural Products and Bioprospecting – publishing natural product research fully open access

Some time ago I have mused where to submit my next manuscript. Yesterday I have decided in favor of the journal Natural Products and Bioprospecting (and luckily my co-authors did not oppose).

I have been a bit skeptical at first (also after reading the Instructions for Authors at that time, but that is another story – let bygones be bygone…). Because of my doubts I have contacted several members of the Editorial Board that I know. All of them have spoken highly of the Editor-in-Chief, Prof. Jikai Liu, as well as the project in general. I also contacted Prof. Liu himself, and he was able to ease my mind.

I think it is great that this journal offers an OA and CC-BY publication model to the natural product research community free-of-charge. I really do appreciate this initiative and think that the Editor-in-Chief has done a great work in realizing this idea.

Now the Natural Product Research community has to be made aware of this journal, so that it gets more widely known!

How “open” are natural product scientists? Part II – Journals

I am currently preparing a manuscript on some isolation and structure elucidation work. It is nothing too thrilling, not even bioactivity will be reported. That is the drawback of working in industry – the really interesting projects must be kept secret. But I love to publish, and so I take the opportunity when I can. Even if the paper will only be of interest to a few fans of cyanobacterial metabolites…

When I got aware of „Open“, I promised myself to publish my coming papers Open Access only. So where should I publish this manuscript? My first thought was PLoS ONE. But as I said, the work is of rather narrow interest, so I think it is not worthy to be published in PLoS ONE, although I have spotted some natural product papers there. Perhaps next time, when I have more to say. For today, let us have a look at my list of natural product research related journals and see if some of these journal might fit.

What are my criteria? First of all, Open Access. Second, the journal should be indexed at least at Chemical Abstracts and PubMed Central – I do not fancy „Google Scholar only indexing“. These two criteria already narrow the choice down to nine journals that would be suitable for classical analytical natural product work:

Journal Publisher Costs
Fitoterapia Elsevier 3000 USD
Journal of Asian Natural Products Research Taylor&Francis 2950 USD
marine drugs MDPI 1800 CHF
molecules MDPI 1800 CHF
Natural Product Research Taylor&Francis 2950 USD
Natural Products and Bioprospecting Springer free
Phytochemistry Elsevier 3000 USD
Journal  of Natural Products ACS 1000-3000 USD
Toxicon Elsevier 3000 USD

Wow. Why does it cost 2000-3000 USD to publish a manuscript OA?! I cannot believe that my manuscript and the surrounding supportive work cause almost a whole month’ work. None of the publishers in this list – in contrast to PLoS ONE – offers a fee waiver on their website, except the ACS, where some discounts for ACS member and subscribing institutions are available.

This might be OK for big industry or well-funded academic groups. But I am doing 95% of the research I publish in my free time. The CEO of the company I work at really supports my scientific work, which I do highly appreciate. But convincing him to spend 3000 USD for a single publication just because I am an OA freak? No way! And I do not have these funds, either. Four hungry kids to feed – 3000 USD for a publication?! My wife would not be too happy… ;-)

Well, there is one journal that is publishing OA free of charge. The journal „Natural Products and Bioprospecting“. What about this one?

Cons:

  • The journal is very young and not that many papers have been published to date.
  • They seem to publish very rapidly (Is it possible to do a full peer review process within 2 weeks? Most of the papers seem to be at about 4-8 weeks, though, which is still rapid but OK…).
  • It is not yet indexed by PubMed Central (but they assured me that they work on this).
  • Most of the members of the editorial board have not published in the journal, yet.

Pros:

  • It is OA free-of-charge (fully sponsored by the Chinese Academy of Science).
  • It is published by a recognized publisher (Springer).
  • It is good to support young journals with a good concept (in this case Natural Products + Open Access)
  • I know some of the editorial board members personally and do not think they would give themselves away for a dump journal.

Taken everything together, I am not sure yet whether the pros or the cons weight heavier. I will surely have a closer look at the journal and perhaps I will decide to submit my next manuscript there…

 

Natural product drug discovery from microalgae

Together with Mark Brönstrup from sanofi-aventis I have written a chapter on “Natural product drug discovery from microalgae” for the book “Microalgal Biotechnology: Integration and Economy“, edited by C. Posten and C. Walter, published by de Gruyter.

I know that this is behind the pay wall – I have signed the author contract before I became Aware of Open… If you want to have a copy of the chapter, just drop me a line. I would be happy about comments on the chapter from anyone interested in this topic.

Edit: What I have learned – Insist on imprimatur. Complicated story why, but the legend of figure 10.8 is wrong and should only read “Mechanism of toxin release from antibody-drug conjugates.”. I have written an email to the publisher and hope that this can be corrected at least in the pdf version of the chapter. After all, it is their mistake that the legend is flawed…

Edit 2: They will correct the figure caption for the pdf file. Thank you, de Gruyter.

How “open” are natural product scientists? Part I – Conference Talks

Four months ago I visited a fantastic conference, the International Conference on Natural Product Research 2012, ICNPR 2012, in New York. It was one of the best conferences I ever visited. I presented two posters there which I later uploaded to figshare (can be downloaded here and here).

Many of the talks were really interesting, and after the conference I contacted 12 speakers if they would share their presentation so that I could have another look at the slides and recapitulate what I had learned.

2 of the scientists answered that they are not willing to share their slides, because some of the material has not been published, yet. Hugh?! How can someone make a publication out of some PowerPoint slides?! And who would be stupid enough to try? And what about those guys in the audience that took pictures of every single slide of every single talk?

Well, at least these two were more polite than the 5 scientists who did not answer at all, even when after a few weeks I kindly remembered them that I had interest to have a second look at their presentations…

This leaves 5 scientists who sent their talks, 3 of them after friendly reminders. Good luck for me that these were the most interesting talks! Funnily enough, 4 of these 5 are professors at the Scripps Institution of Oceanography in San Diego. It might be that American scientists are more willing to share than others; but not all professors from the States I asked did share, though…

Of course this has not been a systematic study of the willingness to share among natural product scientists, but it made me wonder why it is not common standard that all talks are made available to conference attendants after conferences. This would make the experiences of visiting a conference even more pleasant and would enhance the learning effects dramatically.

After making this experience, I decided to share all talks I give, whether people want it or not. :-) And I chose figshare as a platform for this. Of course a slide set is less informative than listening to the talks themselves (especially because sometimes I prefer to show only large pictures and spend some time talking around them…), but anyways…

To put my money where my mouth is: Some weeks ago I talked about „Cyanobacteria in Anticancer Natural Product Research” at the annual meeting of the German Pharmaceutical Society 2012 in Greifswald, Germany. Anyone interested can now have a look at the slides at figshare. If you have any questions on the slides or on cyanobacteria in general, don’t hesitate to comment this blog post or directly the slides at figshare.

List of natural product research related journals, bloggers and tweeters – reloaded

For the original Natural Product Forum I had compiled a list of journals, bloggers and tweeters covering natural product research. This list can now be found here.

If you find some journal / blogger / tweeter is missing but should be on the must-read-list of any natural product scientist, please comment – I will then add your suggestion to the list, keeping it up to date.

The story of the halichondrins

After describing the story of the dolastatins, I thought that also the halichondrins would deserve a post. But I have soon realized that Quintus has already done this very nicely, so that there is no need for me to go into more detail here…

For me it just remains to say that the development of Eribulin from Halichondrin B was a real game changer in the Natural-Product-To-Drug arena.

One of the strongest argument against natural products in drug discovery has always been “It might be a nice hit/lead, but it will never be possible to synthesise such complex compounds economically”. Eribulin simply proves that this is not true. Despite being still rather complex and still having about 20 stereocenters, it is economically feasible to manufacture the compound.

Every decision maker in the natural product sceptic pharmaceutical industry should realise that natural product leads are not that ridiculous after all…