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…

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 I became a friend of “open”

Over the last months, I became more and more aware of the “open” movement. “Open” as in Open Access, Open Source, Open Data, Open Science.

In mid 2011, I had a project where I needed to annotate the tandem mass spectra of some cyclic peptides. So I sat down, fragmented the compound structures “on paper” to see what theoretical fragments I would likely find in my spectra, and compared them with my experimental spectra. This was one of the most stupid and boring tasks I had ever done. And it took me more than 2 full days of work to annotate my two spectra. I mused that for such stupid work computers had been invented.

Of course I had searched for a software tool suitable for cyclic peptide tandem mass spectrum annotation. But I found only two tools that already could do this, and none of them was really suitable for my purpose. Among all the software tools I evaluated, mMass came closest to the tool I had in mind for my purpose, but it was not capable of handling cyclic peptides and had some other restrictions that made it unsuitable as it was. So – just to be prepared for the next time I had to do this task – I contacted the developer of the software, Martin Strohalm, and asked him if he was already planning to implement the features I needed. He had not planned this, but did like the idea to have them implemented. However, when we discussed the first steps, he was reluctant to accept the changes that would be needed to fully implement everything I needed

mMass is Open Source, so I decided to – just for fun – study its code and try to tweak mMass to do what I wanted. mMass is mostly written in Python, so first of all I again had to sit down and learn this language. Luckily for me, at that time my Python-speaking brother-in-law lived at our place and could give me a good start and support if needed.

After many weeks of learning Python, studying the literature for cyclic peptide fragmentation pathways, adding and amending code, in the end the software did what I intended it to do.

I again contacted Martin Strohalm and showed him the results of my work. He did like the additions and agreed to include the features into the official mMass source. He of course – me being a novice programmer – needed to revise most of my code, and to correct bugs I had missed. Many, many emails later we were both satisfied with the novel mMass version, which was then released to the public.

The novel mMass version was superior to all other tools available for cyclic peptide tandem mass spectrum annotations, so I decided that it was also worthwhile to get the whole thing published in an academic journal, as well. Thus I wrote a manuscript and after some polishing by Martin and me, I submitted it to Analytical Chemistry. Why did I choose Analytical Chemistry? One of the two other tools capable of handling cyclic peptides had been published there, so I thought it would be a suitable place for publishing our superior tool. Just as a side remark: this other, published, software is not open source, and the PI has not been willing to share the code. Well, our manuscript was rejected – one of the reviewers did not understand the purpose of the software, and the other one did not agree with some of the implemented features (funny, because the fragmentation pathways implemented were all taken from the peer-reviewed and published literature…). We amended the manuscript to make it more clear and resubmitted it to Analytical Chemistry. It again was rejected, and to be honest, I did not really understand the reviewers problems.

Anyways, I began wondering if Analytical Chemistry was the right place to publish the manuscript. After all, the software and the manuscript were the results of Open Source, so perhaps the paper should be published Open Access. Thus I chose PLoS ONE for the next submission. I have to say that the peer-review was as intense as the one at Analytical Chemistry – but this time we luckily had reviewers who understood the purpose of the software and its potential value. After a minor revision, the paper got published. I would like to use this opportunity to again thank the staff at PLoS ONE for the massive fee waiver. Without this waiver, we would not have been able to publish the manuscript Open Access.

I also presented a poster on mMass at the recent ICNPR 2012 in New York and received positive feedback.

Because mMass is open-source, I could take it as a basis for my work, and together with the original author of the software, we were able to accomplish a great work for scientists dealing with cyclic peptides. For no costs at all for them. This is “Open”! 🙂

And we even made a scientific publication and a poster out of it…

This was my first experience in the “Open” field, and you will find that this is something I will blog about more in the future…