I kept meaning to write last week about GlaxoSmithKline’s decision to open up a database of possible lead compounds against malaria. These were hits from a larger screen that the company ran, and been made unusually public. (Here’s the press release as a PDF). There are about 13,500 structures, apparently. The company is to be commended for doing this, naturally, but I wish that the press coverage would emphasize a few things that it hasn’t so far.
For one, these are not antimalarial compounds, at least not to a medicinal chemist. Some of them might be, but for now, they’re all potential antimalarials, with a long, long way to go. This is all in what most drug discovery organizations call the “hit to lead” stage. Some of these compounds may well be screening artifacts. Others will turn out to work through mechanisms that won’t be useful – they’ll kill malaria parasites, but they’ll kill lots of other things, too. Some of them will hit other targets that aren’t quite as severe, but will still be enough to make them undesirabel. And many others will be too weak to be useful as they are, and turn out, after investigation, to have no clear path forward to making them more potent. And so on.
The most interesting compounds still have a long road ahead. What are their blood levels after various sorts of dosing? Which of those dosage forms are the best – the most reliable, the easiest to make, the most stable on storage? What metabolites do the compounds form in vivo, and what do those do? What long-term toxic effects might they have? How susceptible are they to resistance on the part of the parasites? On top of all these questions are the big ones, about how well these potential drugs knock down malaria under real-world conditions.
This, in short, is what drug development is all about, and it would be good to see some of this brought out in the press coverage. This is what I (and many of the readers of this site) do for a living, and it’s enough to occupy all our time with plenty left over. If you can do this sort of thing, you’re a drug company, and I’m always looking for opportunities to tell people just what it is that drug companies do and to move people past the evil-pharma versus saintly-university mindset. Nature has it right in their editorial:
Meanwhile, universities and other academic institutions should do more to support and reward the sort of translational research required to develop drug leads such as those offered by GSK — even though that work usually does not result in high-profile, breakthrough research papers. In addition, such translational activities provide a means for universities to contribute to public–private partnerships such as the MMV, the Drugs for Neglected Diseases Initiative and the Institute for OneWorld Health.
Universities also have another part to play. Their often aggressive intellectual-property policies can stymie research and development in neglected diseases — they should ensure that their licensing deals with companies make exceptions for royalty-free use of technologies for good causes. That change, too, is beginning to happen — although, when it comes to hogging intellectual property, academics and their institutions are often among the worst offenders. . .