Global Health Primer

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

  1. Edwards DI (1993) “Nitroimidazole drugs – action and resistance mechanisms, I. Mechanism of action.” Journal of Antimicrobial Chemotherapy 31: 9-20.

 

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PIPELINE

Product/Research ProgramDevelopersDiscoveryPre-clinicalPhase IPhase IIPhase III
Benznidazole (chronic Chagas)Pharmaceutical Laboratory of Pernambuco State

 

 

 

 

 

OPC-67683Otsuka Pharmaceutical Co., Ltd.

 

 

 

 

 

PA-824Global Alliance for TB Drug Development
Novartis AG

 

 

 

 

TinidazoleWalter Reed Army Institute of Research

 

 

 

 

FexinidazoleDrugs for Neglected Diseases Initiative
HAT Platform Partners
Sanofi
Swiss Tropical and Public Health Institute

 

 

 

CentanamycinMcGill University
Spirogen Ltd.

 

 

Nitroimidazole backup (HAT)Drugs for Neglected Diseases Initiative
Global Alliance for TB Drug Development
Swiss Tropical and Public Health Institute

 

 

Nitroimidazole backup (VL)Advinus Therapeutics
Central Drug Research Institute
Drugs for Neglected Diseases Initiative
Global Alliance for TB Drug Development
London School of Hygiene and Tropical Medicine
University of Auckland
VL Lead Optimisation Consortium

 

 

Nitroimidazoles TBA-354Global Alliance for TB Drug Development
University of Auckland
University of Illinois - Chicago

 

 

VL-2098Drugs for Neglected Diseases Initiative

 

 

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

  1. TB Alliance Press Release, available here.

 

Get Involved

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 or contact us at globalhealthprimer@bvgh.org.

Databases/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

 

Get Involved

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 or contact us at globalhealthprimer@bvgh.org.

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