Anti-Wolbachia targeted macrofilaricidal drug discovery-lead optimization of lead series chemotypes to deliver novel pre-clinical candidates
Project Completed
 
  • Awarded Year
    2013
  • Awarded Amount
    $1,093,166
  • Disease
    NTDs
  • Intervention
    Drug
  • Development Stage
    Lead Optimization
  • Collaboration Partners
    Eisai Co., Ltd., University of Liverpool, Liverpool School of Tropical Medicine

Introduction and Background of the Project

Lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness) are infections that are caused by parasitic worms.  These diseases affect more than 150 million people globally. The international community agrees that these diseases should and could be eliminated with the correct tools and there are ongoing mass drug administration campaigns underway to achieve this goal. However, in the absence of a drug that can kill adult parasites, current programs require many years of annual (or greater) rounds of drug administration to large populations in the rural communities blighted by these diseases.  We have demonstrated that adult worms can be killed by eliminating a bacterium that they contain called Wolbachia.

 

This project aims to identify new drugs that efficiently kill these bacteria within the worm. This approach has the potential to significantly reduce the timescale of elimination programs, to provide alternatives to current drugs and to deliver tools that can be used in areas where current approaches are failing or cannot be deployed. The antibiotic doxycycline works in this way and proof of concept has already been proven in human field trials. Results were excellent but required 4 to 6 weeks of daily treatment.  Also this drug cannot be used in children and pregnant women who represent a large proportion of the target population. 

 

The goal of this project is to identify potential new drug compounds that act more quickly and more effectively than doxycycline and which could be used in all population groups and to develop these molecules to the stage of international pre-clinical safety testing.

How can your partnership (project) address global health challenges?

Liverpool School of Tropical Medicine (LSTM) is a non-profit charitable institution with a mission to develop and implement new tools and technologies for the control and treatment of tropical diseases.  LSTM has an existing anti-Wolbachia program funded by the Bill and Melinda Gates Foundation and has developed assays and models to test compounds for anti-Wolbachia activity at large scale.

 

The Department of Chemistry at the University of Liverpool (UoL) has made major contributions towards understanding the mechanisms of drug-action of several classes of anti-parasitic drugs.  Over 20 years in partnership, UoL and LSTM have adopted a molecule to man strategy in which research projects have been instigated, operating at all stages of the drug discovery pipeline up to and including clinical trials in humans.  A total of three projects have contributed to the portfolio of the Medicines for Malaria Venture (MMV), an organization that has developed the largest portfolio of anti-malarial drugs in history.

 

Eisai is a Japanese Pharma organization determined to be proactive in improving access to medicines worldwide through partnerships with governments, international organizations and non-profit organizations. Eisai is a signatory of the London Declaration, a coordinated effort to eliminate ten neglected tropical diseases by 2020 through the largest global public-private partnership to date. As it expands its business in both emerging and developing nations, Eisai considers its contributions to the economic development and expansion of the middle-income class through the enhancement of health and welfare in these countries as a form of long-term investment for future growth.

 

The unique partnership of LSTM, UoL and Eisai brings together internationally recognized drug discovery expertise focusing on a totally novel approach to address the current challenges of two parasitic diseases that affect the lives of many millions of people globally.

What sort of innovation are you bringing in your project?

A large library of compounds has been tested for their ability to kill the Wolbachia bacterium.  A number of compounds with good activity have been identified and these compounds will be modified and the tested to improve the drug-like properties and potency against Wolbachia. These discovery activities will be aided by a suite of experimental models that have been validated and shown to translate to the human disease.  Through rounds of chemical modification and testing we will identify lead candidate compounds that have a good balance between activity and other parameters that are essential to a safe and effective drug.

 

The combination of expertise in medicinal chemistry, computational chemistry, biological disease assays and pharmacological drug assessment technologies will lead to the systematic development of new unique compounds. 

 

The approach of killing the parasitic worm by targeting the essential intracellular bacteria is a totally unique approach to parasite chemotherapy and one that offers many advantages over drugs that target worms directly.  Proof-of-concept clinical trials have already shown that this alternative approach works and can reduce elimination timeframes significantly.

Role and Responsibility of Each Partner

The role of Eisai is to use their extensive medicinal chemistry and Drug Metabolism and Pharmacokinetics (DMPK) capacity to synthesize analogues relating to specific chemical templates. These analogues will then be assessed for their anti-Wolbachia potency (LSTM) and DMPK properties (Eisai) with a view to lead optimization and preclinical candidate selection.

 

LSTM is involved in the coordination of this project and in the biological testing of compounds to assess anti-Wolbachia activity. Efficacy testing initially involves in vitro testing using a high-throughput cell assay and compounds with good activity are then tested in an in vitro worm assay to illustrate their anti-Wolbachia potency. Selected compounds with high anti-Wolbachia activity and desired DMPK properties are then assessed in in vivo models against two different worm life-stages, larval and adult, for efficacy. The adult worm model most closely mimics lymphatic filariasis in humans.

 

The University of Liverpool provides synthetic and medicinal chemistry in an advisory capacity to both LSTM and Eisai.