Resistance is futile: hybrid drugs become the latest weapon in the biological arms race

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Researchers at DesignMedix, led by Dr David Peyton, have successfully combined two bioactive compounds to restore the effectiveness of an anti-malarial drug neutralised by the emergence of resistant strains. Their work is paving the way for a new approach to combatting the growing problem of drug resistance.

Malaria is a devastating disease which disproportionately affects emerging economies: it is estimated to cost African nations alone $12bn a year in healthcare costs and loss of economic output. This is compounded into the perfect storm when low-cost treatments are rendered ineffective due to the evolution of resistance in parasite populations. The search for novel therapies and other control methods is ongoing, but Dr David Peyton from Portland State University (PSU) is refusing to surrender in the battle against drug resistance.

With an academic career at PSU which focussed initially on heme proteins, antigen–antibody binding, and virus particle formation, Dr Peyton naturally became involved with public health. On moving to the study of medicinal chemistry, with a particular interest in malaria treatment, he came across the issue of drugs lost to evolved resistance and developed a unique approach to combat the phenomenon.

Determined that chloroquine, the safest and least expensive drug to be used against the malarial parasite, should not be lost, Dr Peyton set out to re-engineer the compound to overcome the parasite’s evolved ability to eliminate the drug. Chloroquine diffuses into the acidic digestive vacuole of the parasite during the asexual stage of its life cycle, when it is within red blood cells degrading haemoglobin for nutrition. In the acidic environment of the digestive vacuole, chloroquine undergoes protonation: because acidity is effectively the number of free protons (H+) in a solution, some molecules will accept these free protons and be changed as a result. As well as the obvious changes in charge and mass from accepting another proton, many chemical attributes of the molecule may also be changed. In the case of chloroquine, these chemical changes mean that it can no longer diffuse back out of the digestive vacuole the way it came in and it builds up, preventing the parasite from eliminating the toxic by-products of haemoglobin metabolism.

The rise of resistance
Due, at least in part, to the use of mass drug administration as a method of controlling malaria in areas with high endemicity (high levels of the disease), selective pressures have resulted in the emergence and spread of drug-resistant strains. Mutations in a particular transmembrane protein effectively render chloroquine useless as a treatment. The transmembrane protein is responsible for exporting chloroquine out of the digestive vacuole and the key mutation results in a significant increase in efflux efficiency (how quickly chloroquine is removed). The P. falciparum chloroquine resistance transporter (PfCRT) has been found to be 40-50 times more effective at removing chloroquine from the digestive vacuole in mutated versus original strains. It is thought that this protein may be using the proton gradient across the vacuole membrane to drive the export of the protonated form of chloroquine. Dr Peyton and his team hypothesised that, by linking a known inhibitor of the transmembrane protein to the chemical skeleton of chloroquine, they could create a revitalised version of an established treatment. The parasite would once again be unable to eliminate the drug and it could form the basis of new mass administration and/or targeted programmes, this time using combination therapies to reduce the likelihood of evolved resistance.

DM1157 returns a tool with chloroquine’s advantages to its previous status as a low-cost and effective weapon in the fight against malariaQuote_brain

The challenges involved in this are significant, however, as any new compound needs to tick all the boxes on the malarial treatment wish list. It must be stable at tropical temperatures to allow for cheap transport and storage in the countries where malaria is endemic. Similarly, with oral dosing as the preferred route of administration for public health programmes, aqueous solubility is of prime importance. But perhaps the most challenging of all, and one of the reasons investment in this area is lacking, it must still be of sufficiently low cost to make it economically viable for healthcare services in developing countries. Confident of their abilities to overcome these hurdles, the team spun out DesignMedix, Inc. a start-up focused on using this technique to resurrect previously effective treatments. With support from the National Institutes of Health and colleagues at PSU, an arsenal of new compounds was developed and each one tested against the malarial parasite.

Dr David Peyton and Rob Jenson in the DesignMedix lab
Dr David Peyton and Rob Jenson in the DesignMedix lab

There are a number of suitable candidates for inhibition of the transmembrane transport protein responsible for the efflux of chloroquine. Known as reversal agents (because they reverse resistance to a drug) they include verapamil, a drug used in the treatment of heart disease and hypertension, and the anti-depressant imipramine. These chemicals are among a large group known to have the right chemical structure to interact in this way with the mutated protein and imipramine was chosen by the team as being particularly suitable for attachment to the chloroquine molecule. Through a small number of simple reaction steps, chloroquine can be restructured to become essentially a hybrid with imipramine, prepared as a free base, or converted to a hydrochloride (or other) salt to promote water solubility.

A new weapon emerges
From more than two hundred similar compounds (termed ‘reversed chloroquines’) created in this way, one was selected. Given the title DM1157, this novel chemical has been put through its paces in in-vitro and ex-vivo studies, as well as having proven efficacy in mice. These impressive results mean it is now ready for its first in-human clinical trials, as it forges a new path to return a tool with chloroquine’s advantages to its previous status as a low-cost and effective weapon in the fight against malaria. With the right support, the success of DM1157 could open the way for the same approach to be used across a range of treatments and pathogens, potentially returning many drugs to therapeutic use.

Malaria remains a devastating disease across much of the developing world, preventing many emerging economies from realising their full potential. In spite of intense research efforts and new control methods, the fight against this destructive protozoan will continue to need novel tools in the shape of drugs, insecticides and perhaps even vaccines. DM1157 will be one such weapon which, in combination therapies with other effective treatments and alongside public health programs, could give us the upper hand in the battle for eradication.

What led you to look into chemical synthesis as a means of overcoming drug resistance?
The ‘gold-standard’ drug, chloroquine, had been lost, at least to its traditional use, and so we had to find another way forward. The simplest and least expensive way to salvage the best features of chloroquine was to make a ‘better chloroquine’, at least better given the current state of drug-resistance across the developing world. This meant chemical synthesis, because there is no other way to get there.

In your view, what are the main challenges facing the development of drugs for the emerging economies market?
Bridging the ‘gap’ that exists between discovery and marketing. There are resources from agencies such as the NIH for university researchers, and even funds available through programmes (for example, the SBIR or STTR mechanisms in the US) that work quite well at the early stages. But it becomes more challenging to bridge the efforts as they become more expensive and depend on resources that are not internal to universities or small businesses, such as GLP service providers. These can be unfamiliar to traditional researchers and relatively expensive, making it challenging for the usual grant mechanisms to fund fully. Then, there is the obstacle of bringing the drug through the human trials – which will require teams and financial resources that are well beyond what almost any researcher originally involved in the enterprise of drug discovery would have thought about. For malaria, there are entities that can help, but that is less true for other markets.

What makes you confident that malaria will eventually be eradicated?
That is a very large question. I am confident that malaria can be eradicated. I am confident that malaria will be eradicated just as long as sufficient resources are dedicated to the effort for as long as it takes. I also believe that this is a very serious topic, and that we should not make the mistake of making it seem easier to do this than it will be. Unless there are some unforeseen developments, the eradication effort for malaria will take decades and constant dedication. But it will be worth it. The alternative is continual evolution of resistance against each generation of newly-developed tools.

What would make the biggest difference to the successful development of DM1157?
Partnering with a company with another drug in its pipeline, such that these drugs make sense as a combination to move through the next stages of the development and approval process. Hopefully, such a company would have the resources or connections to facilitate marketing throughout the developing world populations where malaria drugs are needed.

What one piece of advice would you give to someone considering creating a start-up?
Don’t do it by yourself. A scientist needs help with the ‘business side’ of the process, and everything you do takes time. Without my partners in this enterprise, I’m sure we would have not made the progress we have.

Research Objectives
Dr David Peyton uses pioneering techniques to restore the effectiveness of drugs. His work focusses on low-cost, safe treatments for malaria.

Funding

  • NIH:NIAID
  • ONAMI (Oregon Nanoscience and Microtechnologies Institute) [http://onami.us/]

Collaborators

  • Dr Michael Riscoe, Portland VA Medical Ctr and OHSU
  • Dr Jane Kelly, Portland State
  • Dr Roland Cooper, Dominican University of California
  • Dr Jutta Marfurt and Dr Ric Price
  • Dr Steven Burgess
  • Dr Lynn Stevenson and Dr Sandra Shotwell, co-founders of DesignMedix, Inc. [http://www.designmedix.com]

Bio
peytonheadshotAfter a PhD at UCSB in 1983, and postdocs at Weill Cornell Medical College and UCD, Dr David Peyton began his academic career at PSU, focused on heme proteins, antigen–antibody binding, and virus particle formation. He then moved into medicinal chemistry to study malaria and co-founded the company DesignMedix, Inc. He also studies the toxicology of tobacco products, including e-cigarettes. His career has thus become concerned with public health.

Contact
David H. Peyton, PhD
Room 323B SB-1 (office behind lab)
Professor of Chemistry
Portland State University
Portland, OR 97207-0751

E: peytond@pdx.edu
T: +1 503 725 3875
W: https://www.pdx.edu/profile/david-peyton
http://www.designmedix.com

For more information on malaria visit:
https://www.niaid.nih.gov/topics/malaria/Pages/default.aspx

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