Open Source Malaria on World Malaria Day 2021

[mattodd]

Hi all,

World Malaria Day always creeps up on me and always seems to happen when lots of other things are going on. So here's a delayed post (also being sent out to the email list) on some of the work that's been going on in the last year in Open Source Malaria (OSM).

If you're not familiar with how OSM works then you can read about the basic ideas. The aim of OSM is to discover new medicines for malaria using an open approach that encourages people to get involved in the research as it's happening, rather than after it's completed, and which explicitly licences its outputs as CC-BY-4.0 thereby clarifying that people can do whatever they want with the outputs, provided they cite OSM. We've been doing this now since about 2011 - come to think of it maybe we should soon mark the decade since the first experiment.

OSM has focussed on four series so far, summarised below. The first one was taken as far as we could (within the constraints of the resources we had) and then we published it. I say "we", and that means a highly disparate set of people who came together to advance the science. There's always been a grant operating (e.g., mix of government funds and MMV resources) that supported one person in lab, but everyone else has come to that core to contribute their time and expertise, from junior students to pharma company professionals.

The second series was paused when we found out (on the grapevine, I forget how) that another group was looking at it, in a closed project. If there's one thing we don't want to do in OSM it's unnecessary duplication of work.

The third series is interesting. We worked hard for a couple of years making analogs of what is a super-promising starting point, originally discovered by GlaxoSmithKline at Tres Cantos (as for the first two series). Everything we did made the potency drop from 100 nM to zip. So we stopped. But I remember a conversation I had a few years ago with Jeremy Burrows from MMV where we were struck, despite the absence of any potent analogs, by the promise of that starting point (OSM-S-106), so we asked MalDA to look into how the molecule might be working. They came up with data suggesting that the molecule has a new target: asparagine tRNA synthetase (NRS). Suddenly, 106 became a more exciting molecule. Tha Bhebhe in my lab has been trying to modify the core of the structure, and Leann Tilley in Melbourne has done some beautiful work to show that NRS is very likely to be the mechanism by which the molecule kills the parasite. Intriguingly in parallel we discovered that the molecule also inhibits another target, carbonic anhydrase. Sally-Ann Poulsen and Sarah Muller obtained a crystal structure of OSM-S-106 binding the human version of this target (below). There's lots of other data obtained by others here, too, and we're in the middle of putting it all together. When a project like this is open, it's hard to present it because there's significant uncertainty and things are changing quickly, but that's the nature of research, obviously. I think the remainder of this year will bring us clarity, but the molecule is super-neat and is currently being evaluated in a mouse to determine its basic pharmacokinetic properties.

Series 4 (originally discovered by Pfizer) has been the busiest series. The main medchem campaign is nearly ready for submission and we're tantalisingly at the stage of having promising molecules that are just not quite potent enough for a third mouse evaluation - everyone was super excited about the OHOH molecule we discovered with Scott Obach's biofunctionalisation team at Pfizer, but the potency couldn't be recapitulated with a re-synthesised sample. Sub-projects in this series were published on some intriguing synthetic chemistry, some hardcore medchem around bioisosteres and a big project we ran to figure out whether artificial intelligence and machine learning methods could help us predict active compounds even though we had no target crystal structure (the answer is "yes"). This latter project is ongoing, in the sense that there are still suggestions coming in that we'd like to act upon, and we've been thinking we need to up-scale this approach of involving AI/ML companies in the design phase. Because the project is open, those companies are able to demonstrate what they're able to do, while helping a project aimed at improving global health. A win-win, provided we can actually make the suggestions to see if they work!

We started a Series 5 after Helen Hailes at UCL donated some molecules based on a tetrahydroisoquinoline core that was reported to be active, but as things stand we have not observed the activity even with re-synthesised samples, so we may need to park that series early.

If you've a set of molecules you'd like to "immortalise" in the public domain as OSM Series 6 or 7 (e.g. if it's a paused project, or some early stage data, etc) then you're are completely free to start (and control) it, and we are now pretty good at handling such series and helping the community to gather around the data. You should also check out MMV's Malaria Libre initiative.

But... so what? What if a molecule is promising? How can you possibly take a public domain unpatented molecule through to patients? Who would pay for the development? The clinical trials? An unpatented molecule has never been discovered and developed in public and been taken through to market to benefit patients. Well, I co-founded a company, M4ID Pharma, to achieve exactly this, and you can read about the business model. So there is a good plan in place, and all we need to do is try it out on some real candidate molecules.

But...what about vaccines? There has been a tremendous recent development on that front. I hope it works out. Inexpensive, prophylactic medicines will always be a key part of the armoury we need to fight what is still one of the world's most dreadful diseases. If OSM can help advance some of those medicines, as part of a research effort that involves us all, then that would I'm sure make all our many and varied contributors very happy. My primary thought on World Malaria Day was my gratitude to all OSM contributors and my enormous sense of enjoyment in working with that community.

Best,

Mat

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