Identification and prioritization of novel anti-Wolbachia chemotypes from screening a 10,000-compound diversity library
| Autor: | Johnston, Kelly L., Cook, Darren A. N., Berry, Neil G., David Hong, W., Clare, Rachel H., Goddard, Megan, Ford, Louise, Nixon, Gemma L., O’Neill, Paul M., Ward, Stephen A., Taylor, Mark J. |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Drug Evaluation Preclinical SciAdv r-articles Computational Biology Reproducibility of Results Diseases and Disorders biochemical phenomena metabolism and nutrition Anti-Bacterial Agents Workflow Small Molecule Libraries Drug Development parasitic diseases Drug Discovery bacteria Cluster Analysis Humans Health and Medicine reproductive and urinary physiology Research Articles Wolbachia Research Article |
| Zdroj: | SCIENCE ADVANCES Science Advances |
| Popis: | Screening of 10,000 compounds reveals anti-Wolbachia chemotypes with potential to be developed into new drugs for two NTDs. Lymphatic filariasis and onchocerciasis are two important neglected tropical diseases (NTDs) that cause severe disability. Control efforts are hindered by the lack of a safe macrofilaricidal drug. Targeting the Wolbachia bacterial endosymbionts in these parasites with doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimens and contraindications restrict its widespread implementation. The Anti-Wolbachia consortium aims to develop improved anti-Wolbachia drugs to overcome these barriers. We describe the first screening of a large, diverse compound library against Wolbachia. This whole-organism screen, streamlined to reduce bottlenecks, produced a hit rate of 0.5%. Chemoinformatic analysis of the top 50 hits led to the identification of six structurally diverse chemotypes, the disclosure of which could offer interesting avenues of investigation to other researchers active in this field. An example of hit-to-lead optimization is described to further demonstrate the potential of developing these high-quality hit series as safe, efficacious, and selective anti-Wolbachia macrofilaricides. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|