What is DNA Damage?
DNA damage is the result of irreversible modification of DNA nucleotides or breakage of DNA strands. Although repair systems can fix minor damage, cell death results if the damage cannot be repaired.
Overview
DNA integrity is essential for cellular survival. Most healthy human cells are equipped with repair systems that can fix minor damage to DNA, but cells that undergo constant growth, such as cancer cells and a variety of unicellular pathogens, are more susceptible to DNA damage. This concept led to the development of DNA damage-inducing agents as therapeutics.
Existing Products
Cancer
Induction of DNA damage that blocks replication and leads to apoptosis/cell death is one of the cornerstones of cancer treatment. Radiation therapy, for instance, uses ionizing radiation to generate free radicals that can irreversibly and significantly modify DNA. Beyond radiation therapy, chemotherapies also often make use of DNA damage mechanisms. For instance, alkylating agents that irreversibly modify a variety of biological molecules, including DNA, are used in cancer treatment. These products include cyclophosphamide, chlorambucil, and ifosfamide.
Bacterial and Parasitic Protozoan Infections
Nitroimidazoles are a class of small molecules with broad utility for the treatment of parasitic protozoa and bacteria. There are several factors that contribute to the efficacy of nitroimidazoles to target these microorganisms over host cells:1
| Drug | Susceptible Organism Classes | Specific Indications |
| Metronidazole (5-nitroimidazole) | Bacterial infections | Anaerobic abscess Bacterial meningitis Bacterial vaginosis Anaerobic infection |
| Parasitic protozoa | Amebic dysentery Amebic liver abscess Trichomoniasis |
|
| Tinidazole (5-nitroimidazole) | Bacterial infections | Bacterial vaginosis |
| Parasitic protozoa | Amebic infection Amebic liver abscess Giardiasis Trichomoniasis |
|
| Benznidazole (2-nitroimidazole; Ex-USA only) | Parasitic protozoa | Chagas disease |
References
- Edwards DI (1993) “Nitroimidazole drugs – action and resistance mechanisms, I. Mechanism of action.” Journal of Antimicrobial Chemotherapy 31: 9-20.v
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Pipline
Analysis
Nitroimidazole-related compounds, such as metronidazole, tinidazole, and benznidazole, have been used successfully to treat several parasitic and bacterial infections, confirming that inducing DNA damage is a viable strategy for the treatment of neglected diseases. The most advanced new nitroimidazole-related compounds in development are (1) PA-824 in phase II for tuberculosis, and (2) fexinidazole in phase I for human African trypanosomiasis (HAT). In July 2010, the Global Alliance for TB Drug Development (TB Alliance; the PDP developing PA-824) entered into a royalty-free licensing agreement with the Drugs for Neglected Diseases Initiative (DNDi; the PDP developing fexinidazole).1 The agreement allows DNDi to evaluate nitroimidazole-related compounds originally developed for tuberculosis for the treatment of other neglected diseases, including Chagas disease, HAT, and leishmaniasis. This is the first agreement of its kind between PDPs.
None of the on-market or late-stage clinical nitroimidazole compounds have been directly repurposed across neglected diseases. For instance, although benznidazole is currently in use for the treatment of Chagas disease, it is not in use for the treatment of the closely related parasite that causes HAT. The parasites that cause Chagas disease and HAT are highly related, but the pathogenesis of the two parasites is distinct. In late stage HAT, parasites are sequestered in the central nervous system, requiring medications to cross the blood brain barrier. In contrast, the parasites that cause Chagas disease infect the tissues of the heart, intestines, and esophagus. Drugs for these two related diseases require distinct distribution properties despite having identical mechanisms of action.
DNA alkylating agents in use for the treatment of cancer are associated with severe side effects and are therefore unlikely to be directly repurposed for the treatment of neglected diseases. There are no clinical stage DNA alkylating agents in development for neglected diseases. However, one product, AS-1-145/centanamycin, is in pre-clinical development by Spirogen and McGill University for the treatment of malaria.
By sharing safety, biodistribution, and efficacy data across the cancer, antibacterial, and anti-parasitic drug development communities, the full potential of DNA damage inducing compounds can be explored.
| Strengths | Weaknesses | Opportunities | Risks | |
| Nitroimidazoles | ||||
| Relevant neglected tropical diseases: Chagas (Benznidazole, on market) Tuberculosis (PA-824, phase II and others) HAT (Fexinidazole, phase I) |
On market products for both neglected tropical disease and non-neglected tropical disease indications Small molecule compound libraries associated with these drug discovery programs exist for further screening |
General mechanism of action contributes to side effects/toxicities Toxicity to host cells may limit utility |
Screening compound libraries generated during cancer, antibiotic, or anti-parasitic drug development against additional neglected tropical diseases Share knowledge from previous drug development program regarding structure activity relationships, distribution, and toxicity |
Differences in pathogenesis between neglected tropical diseases will likely require redevelopment of compounds for each disease rather than direct repurposing |
References
- TB Alliance Press Release, available here.
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Database Resources
There are several resource for additional information on DNA damage causing agents, including:
Assays
Several assays have been developed to monitor DNA damage. These assays may be directly applicable to some neglected tropical diseases but will also be important for monitoring potential host cell toxicity during the drug development process. Assays include:
- Comet Assay by Trevigen – single cell DNA gel electrophoresis
- PARP (poly-ADPribose polymerase) Assay by Amsbio– PARP plays a role in DNA repair, PARP Assay Kits measure incorporation of biotinylated PAR onto histone proteins, allowing screening of PARP inhibitors & measurement of PARP activity in cell and tissue extracts. PARG Assay Kits allow screening of PARG inhibitors & measurement of PARG activity in cell extracts.
- TUNEL assay (many manufacturers) - measures DNA strand breaks. Two sample protocols can be found here and here.
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To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.