TB or Not TB - Are Covalent Drugs the Answer?

Story by Hamish Howard

Faculty of Science, 2018

Introduction

Intellectual property, once considered of no value to a major pharmaceutical company, is now poised for development into new antibiotics which could aid the response to a global health emergency.

Covalent Drugs

Unless you have a background in chemistry, it’s unlikely that you’ve ever heard of covalent inhibitors. Yet you may have heard of aspirin—or perhaps penicillin? Although technical, the term covalent inhibitor is useful in explaining how these drugs function. They target specific proteins, with which they form covalent bonds, inhibiting their activity. Confused?

Proteins, in this context, are a class of molecules that carry out a range of biological functions, and many biological processes are reliant on proteins carrying out various tasks. Covalent drugs attach themselves to specific proteins, preventing them from carrying out their tasks. In other words, covalent drugs act as the metaphorical ‘spanner in the works’. Still confused? Perhaps take an aspirin and let me explain further.

Aspirin, the popular name for acetylsalicylic acid, is the World’s most widely used medication. The drug targets a specific protein (cyclooxygenase), with which it forms a covalent bond, inhibiting the production of biological compounds (prostaglandins and thromboxanes) involved in a range of physiological processes that one would associate with the use of aspirin, e.g. pain transmission, blood clotting.

Covalent drugs have had a major positive impact on human health, yet their development has been very limited. Despite covalent drugs proving highly profitable, the pharmaceutical industry has largely avoided their development. This reluctance appears to have resulted from limitations surrounding the rational design process of such drugs, which have heightened safety concerns.

These safety concerns were primarily established through pioneering work carried out in the 1970s. They include the potential for off-target reactivity, idiosyncratic toxicity and allergic reactions. For example, in those sensitive to aspirin idiosyncratic toxicity can result in asthma attacks.

Given many examples of successful covalent drugs and the recent emergence of new principles for rational design, the concerns of the pharmaceutical industry are now viewed by many as unwarranted, or at least overstated. As a result, many are predicting a resurgence of interest in this important class of drugs.

A Global Health Emergency

Tuberculosis (TB) is one of the top ten causes of death worldwide according to the World Health Organisation (WHO) who declared the infectious disease a "global health emergency" in 1993. TB is usually caused by the bacterium Mycobacterium tuberculosis (MTB) and has infected approximately one-quarter of the global population.

While the disease typically affects the lungs and can also affect other parts of the body, it is most commonly present in latent form. Latent tuberculosis is an inactive, non-symptomatic, non-contagious form of TB which can develop into active TB.

The only available TB vaccine is the most widely used vaccine in the world, with over 90 percent of all children being vaccinated. In children, this reduces the risk of infection by 20 percent and the risk of disease from infection by close to 60 percent. Management of the disease itself is almost entirely dependent on the use of antibiotics. However, rates of antibiotic resistance are increasing.

The “public health crisis and health security threat” that is antibiotic resistance in TB is illustrated by the extent of terminology. Multidrug-resistant TB (MDR-TB) is defined by resistance to the two most effective first-line antibiotics (rifampicin and isoniazid). Extensively drug-resistant TB (XDR-TB) is defined by resistance to three or more of the six second-line drug classes. Totally drug-resistant TB (TDR-TB), first detected in 2003, is resistant to all currently used drugs.

The WHO’s ‘End TB Strategy’ aims to ensure that no family is burdened with catastrophic costs due to TB, to cut new cases by 80 percent, and to reduce TB deaths by 90 percent by 2030. Although incidence is falling by approximately two percent per year, a decline of four to five percent must be achieved in order to reach these goals. The strategy outlines three strategic pillars required to end the epidemic:

1. Integrated patient-centred care and prevention

2. Bold policies and supportive systems

3. Intensified research and innovation.

Innovation to End an Epidemic

Dr Lawrence Harris, Senior Scientist at Victoria’s Ferrier Research Institute, completed a DPhil (PhD) in synthetic organic chemistry at the University of Oxford in 2009 and joined the carbohydrate chemistry team (now the Ferrier Research Institute) immediately afterwards.

Although Dr Harris has worked on many other interesting chemistry projects, including a similar project with potential application to the treatment of Alzheimer’s disease, he considers his work on TB to be the most exciting and potentially the most rewarding.

The discovery of a new antibiotic, a TCI known as 2-VIC (2-vinyl-D-Isocitrate), could pave the way for the development of new drugs to treat TB. 2-VIC targets and inhibits ICL (isocitrate lyase) proteins. These proteins are essential to the growth of MTB in humans. Fortunately, ICL proteins are found in all strains of TB but are absent in mammals. This greatly reduces the potential for undesirable effects to result from the drug’s use. Additionally, the mechanism by which the drug inhibits the protein (known as suicide inhibition) further reduces the likelihood of negative side effects.

The Future of Covalent Drugs

There are many good reasons for society to pursue the development of new covalent drugs. Improving the treatment of diseases such as TB and safeguarding against the disastrous implications of antibiotic resistance are both highly consequential endeavours that will help to ensure the continued flourishing of human civilisation.

However, the lack of funding for this work poses a significant barrier to future drug development. In fact, the intellectual property that Dr Harris’s work is founded on was initially developed by a major pharmaceutical company before being discarded due to a lack of interest in such development. Having now achieved a significant breakthrough, the further development of what could be a new class of antibiotics used in the treatment of TB will depend on Dr Lawrence Harris and his team acquiring the necessary funding.

A proposal for a funding grant from the Royal Society’s Marsden Fund has been submitted and work is now under way on a new proposal which will be submitted to the National Institute of Health in the USA.

  • <p>A poster from the 1930s warning of latent tuberculosis. https://www.nlm.nih.gov/exhibition/visualculture/tuberculosis.html</p>
  • <p>Dr Lawrence Harris. Image courtesy of Victoria University of Wellington.</p>

Victoria University of Wellington

Kelburn, Wellington 6012, New Zealand