Slow Onset Inhibition of KasA by Thiolactomycin: Mechanistic Insights and Lead Optimization for Anti-Bacterial Drug Discovery

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Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Documento escrito por un elevado número de autores/as, solo se referencia el/la que aparece en primer lugar y los/as autores/as pertenecientes a la UC3M.The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

AbstractThe identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.</jats:p

Slow Onset Inhibition of KasA by Thiolactomycin: Mechanistic Insights and Lead Optimization for Anti-Bacterial Drug Discovery

Stony Brook University Libraries. SBU Graduate School in Chemistry. Lawrence Martin (Dean of Graduate School), Peter J. Tonge Ph.D. Advisor Professor, Department of Chemistry, Daniel P. Raleigh Ph.D. Chairman of Defense Professor, Department of Chemistry, Iwao Ojima Ph.D. Distinguished Professor, Department of Chemistry, Lizbeth Hedstrom Ph.D. Professor, Department of Biochemistry Brandeis University

Crystal Structures of Mycobacterium tuberculosis KasA Show Mode of Action within Cell Wall Biosynthesis and its Inhibition by Thiolactomycin

SummaryMycobacteria have a unique cell wall consisting of mycolic acids, very-long-chain lipids that provide protection and allow the bacteria to persist within human macrophages. Inhibition of cell wall biosynthesis is fatal for the organism and a starting point for the discovery and development of novel antibiotics. We determined the crystal structures of KasA, a key enzyme involved in the biosynthesis of long-chain fatty acids, in its apo-form and bound to the natural product inhibitor thiolactomycin. Detailed insights into the interaction of the inhibitor with KasA and the identification of a polyethylene glycol molecule that mimics a fatty acid substrate of approximately 40 carbon atoms length, represent the first atomic view of a mycobacterial enzyme involved in the synthesis of long-chain fatty acids and provide a robust platform for the development of novel thiolactomycin analogs with high affinity for KasA