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TB Drug Discovery
Because of the emergence of drug-resistant strains, tuberculosis has returned as a global health threat in the 21st century. One of IDRI's long-term goals is to aid in the discovery and development of new drugs that will more effectively respond to new forms of the disease.
To this end, we have joined the Lilly TB Drug Discovery Initiative, a unique public-private collaboration dedicated to accelerate early-stage TB drug discovery. This multi-faceted program consists of screening for new drugs and inlicensing existing drug candidates for development. This program complements IDRI's other efforts in the immunotherapy of TB.
High Throughput Screening
When a disease target is identified from our discovery biology programs, or from a collaborating laboratory, assays are developed and validated for high-throughput screening (HTS). The IDRI robotic screening center consists of two parts. One is a purely biochemical screening operation and the other can screen compounds against virulent M. tuberculosis in a BSL-3 lab. IDRI’s BSL-3 facility allows screening of virulent Mtb with an expertise that only exists in a handful of locations worldwide.
The following approaches are available to IDRI, and all are being deployed:
· Physiology-based screening, which relies on physiological readout to screen and profile compounds, usually on cell-based assays, and is independent of target identity.
· Target-based biochemical screening, which is a paradigm based on knowledge of the function of a potential therapeutic target protein and its role in the disease. It involves biochemical assays on the protein in a cell-free system.
· Target-based whole cell screening, which is a hybrid of the two. Bacterial strains are constructed that over- and/or under-express a target protein. If a given compound is affecting cell growth via that target, it will exhibit different MIC values against the different strains. This should greatly improve the quality of the hits coming from screens by narrowing them down to those that specifically inhibit through the mechanism being studied
IDRI researchers will use these techniques to discover new prototype molecules from a library of compounds provided by Eli Lilly & Company. Other compound libraries will be accessed as well. Efforts will be complemented with medicinal chemistry expertise to improve those molecules, generating more potent and deliverable analogs.
IDRI’s screening centers are automated with instrumentation and data systems that expand lead discovery efforts. IDRI’s robotics are designed for running cell-based screens as well as biochemical screens of purified protein targets.
Staff
Allen Casey, Group Leader, High Throughput Screening / Robotics
Ed Kesicki, Director, Small-Molecule Drug Discovery
David Roberts, Scientist I
Juliane Ollinger, Postdoctoral Scientist
Eli Lilly and Company has given $15 million to establish The Lilly TB Drug Discovery Initiative. Included in the donation is $9 million in-kind, including fully equipped high throughput screening and chemistry laboratories, research tools, databases, and scientific and technical expertise, plus $6 million in cash over five years to seed the organization. In addition to the funding, Lilly has opened access to its greatest assets, a library of 500,000 compounds and chemistry research tools.
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