- RFP Year2019
- Awarded Amount$953,159
- Development StageLead Identification
- Collaboration PartnersChugai Pharmaceutical Co., Ltd., The Global Alliance for TB Drug Development
- Past Project
Introduction and Background of the Project
Chugai Pharmaceutical Co., Ltd. and TB Alliance collaborated in a program under a sponsorship of the GHIT. A set of natural products were discovered to have potent activity against Mycobacterium tuberculosis (M.tb), and they appear to be unprecedented in the pipelines for TB drug development. They are now ready to be examined further in the next phase of drug development.
The main objective of this project is to develop compounds we discovered through our process of testing natural products against M.tb, the bacteria that causes TB. This involves not only improving the potency of the compounds against M.tb but improving their pharmacokinetic properties and safety liabilities so that we can demonstrate their activity in animal models. We plan to identify a compound at the end of the two-year period to move to the next phase of development, known as lead optimization.
The original hits were discovered from natural products that were produced by microorganisms through a fermentative process. For the next step, instead of fermentation processes, we plan to employ synthetic chemistry to prepare a large number of analogues in a relatively short time. The new analogues will be tested for potency, metabolic properties, safety, and eventually efficacy in mice. We are already investigating how these hit compounds kill M.tb and once this is deciphered, it should inform the design of new analogues by taking the structure of the target biomolecule into account.
How can your partnership (project) address global health challenges?
According to the most recent data from the World Health Organization, in 2018 an estimated 10 million people fell ill with TB. Although we have drugs that can cure drug-sensitive TB, patients must receive daily treatment for 6 months or longer. This extraordinary length of treatment can cause poor patient compliance leading to the emergence of drug-resistant M.tb strains. In the same year, approximately half a million people fell ill with drug-resistant forms of TB. We need new drugs to combat resistant strains, as well as to shorten the treatment duration for patients with drug-sensitive strains. The hit compounds are active against resistant strains tested to date. If they can be developed successfully, it will enable new TB regimens made up of all-new drugs to become a treatment option for healthcare providers.
What sort of innovation are you bringing in your project?
We identified the hit compounds by focusing on natural products which were historically a rich source of antibiotics. Screening natural products, however, has been deemphasized in recent years in the face of parallel syntheses and target-based screening. By returning to this rich source of novel antibiotics and at the same time applying the most advanced synthetic technology, we believe we can combine the merits of these two approaches. By the data on hand it is suspected that these compounds have a new mechanism of action as M tb-active agents. We will also make use of computational approaches for design and analysis of new analogues once the target is identified.
Role and Responsibility of Each Partner
The Chugai scientists will provide their expertise in drug development in a wide variety of therapeutic drugs. They will contribute in designing new analogues and selecting safety assays to carry out. The TB Alliance scientists will provide expertise in natural product chemistry and designing TB-specific biological studies. The two teams will communicate by frequent teleconferences and face-to-face meetings. The syntheses will be carried out by a contract research organization and the main TB biological studies will be carried out at the University of Illinois in Chicago. Both organizations will bring their industrial and academic contacts to accelerate the development of hits.