Making chemistry matter: The value of discovery

Prof Colin J Suckling OBE DSc FRSE from the Department of Pure & Applied Chemistry, at University of Strathclyde, explains the value of discovery when it comes to making chemistry matter

In the previous issue of Open Access Government, I wrote about our scientific philosophy at Strathclyde and the value of combining research in medicinal chemistry with chemical biology. These continue apace but equally important at the University of Strathclyde whose defining strap-line is ‘A place of useful learning and for the good of mankind’, which is the translation of discoveries into products that do worthwhile things, in other words, development and commercialisation. Firstly before I turn to commercialisation, what are the potentially useful outcomes of our research awaiting development?

Our primary focus has been anti-infective compounds responding to the global need for new medicines to combat antimicrobial resistance in all its forms. The approach uses compounds that bind to DNA, so-called minor groove binders and those discovered at Strathclyde are referred to as S-MGBs. We have tackled bacterial, fungal and parasitic infection with some success taking individual S-MGBs forward as far as experiments in animal models of disease that demonstrate their ability to cure or reduce the impact of infectious disease, so-called proof of concept experiments.

making chemistry matter
A representation of S-MGBs (sticks) bound to the minor groove of DNA (solid)

By far the most advanced is an S-MGB for the treatment of Clostridium difficile associated diarrhoea being developed by our partner company, MGB Biopharma and has now reached the stage of a Phase 2a clinical trial. This, however, is the only S-MGB currently in the clinical commercial domain. On the other hand, many others have successfully demonstrated proof of concept in relevant animal models of disease. With respect to parasites, four compounds have been found to be able to cure trypanosome infections in mice through experiments carried out at the University of Glasgow in Mike Barrett’s laboratories and the University of Dundee in Kevin Read’s laboratories. This means that we are now at the stage of selecting candidate compounds and preparing for preclinical studies.

It would be a mistake to think that we are only concerned with infectious diseases in the developed world. The antitrypanosome project’s focus is Animal African Trypanosomiasis (AAT) and aims to help some of the poorest farmers in the world to have healthy cattle herds. There are other significant international extensions too. Working with Ariel Silber at the University of Sao Paulo, Brazil, it has been found that one of our best antitrypanosomal compounds is effective against the South American species of parasite, T. cruzi, that is responsible for Chagas disease. In addition, we have a new collaborative project with the National Chemical Laboratory, Pune, India looking at the activity of our S-MGBs against the related parasite, Leishmania, which still causes widespread distressing disease in rural India.

S-MGBs are also effective with anti-fungal activity against Aspergillus spp. and Candida spp. as shown by studies with Mike Bromley of the University of Manchester. And most strikingly, we have recently learned from our collaborator Reto Guler at the University of Cape Town, South Africa, that two of our S-MGBs are effective at reducing the bacterial burden in a mouse model of tuberculosis without causing toxic or tissue-damaging effects to the animals. Very recently, we opened up the possibility of treating bacterial bovine mastitis with S-MGBs in partnership with the Veterinary School of the University of Glasgow.

There are, nevertheless, some important gaps; high anti-Gram negative bacterial activity is still a problem for S-MGBs but our current discovery projects are beginning to break into this field too. A portfolio of such active compounds in such important fields from one academic chemical laboratory working with expert and resourceful biological partners around the world is a remarkable asset and has led to many significant academic publications. The challenge now is to go further and to bring these S-MGB discoveries into development so that they can be a benefit to people and animals in the clinic.

Turning now to development and commercialisation, if we did not live in a world in which we have to pay for what we do, we could develop without commercialisation. But that’s eutopian. So one way or another we have to find a way for development to lead to distribution and some sort of market. As mentioned above, one S-MGB has already been developed by our partner company, MGB Biopharma, who have set up a current Phase 2 clinical trial for Clostridium difficile associated diarrhoea (CDAD). GalvMED (Global Alliance for livestock and veterinary medicine) has contributed to the costs of the AAT project along with BBSRC. This, however, is the only direct industrial involvement so far.

It is well known that big Pharma has been reluctant to invest in anti-infectives both because of the scientific challenge and the commercial problem of recovering investment and, bluntly put, making a profit. As academic scientists, we can’t do a great deal about this. We’ve fulfilled our responsibilities by creating a very extensive collection of anti-infective compounds and validating their potential in animal models of disease. That’s just about as far as an academic group can go with academic funding. But we don’t want things to stop here; we want to see our compounds out there in action in the clinic or in the field.

Translational funding has always been difficult to manage and the difficulties are multiplied with so many active compounds to treat a wide range of serious infectious diseases. Moreover, the unconventional target and mechanism of action of S-MGBs, with respect to industry norms, leads to great caution on behalf of commercial funders, the fact that one of our early compounds has reached a Phase 2 clinical trial notwithstanding. Our experiments also show that S-MGBs are also very resilient to the development of resistant strains. They are, therefore, very much compounds for the antimicrobial resistance era. Much public and political rhetoric has been expended on the crisis of antimicrobial resistance. In the S-MGBs, we have a class of compounds that can make a real contribution to mitigating the crisis in many fields of infection. Our search, not so much for compounds now, but for translational funding continues.

making chemistry matter
Colin Suckling in his office at the University of Strathclyde

 

Please note: This is a commercial profile

Prof Colin J Suckling OBE DSc FRSE

Research Professor of Chemistry

Department of Pure & Applied Chemistry, University of Strathclyde

Tel: +44 (0)141 548 2271

www.strath.ac.uk/chemistry/

LEAVE A REPLY

Please enter your comment!
Please enter your name here