Probing the S2鈥?Subsite of the Anthrax Toxin Lethal Factor Using Novel N-Alkylated Hydroxamates
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- 作者：Elbek K. Kurbanov ; Ting-Lan Chiu ; Jonathan Solberg ; Subhashree Francis ; Kimberly M. Maize ; Jenna Fernandez ; Rodney L. Johnson ; Jon E. Hawkinson ; Michael A. Walters ; Barry C. Finzel ; Elizabeth Ambrose Amin
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：November 12, 2015
- 年：2015
- 卷：58
- 期：21
- 页码：8723-8733
- 全文大小：664K
- ISSN：1520-4804
文摘
The lethal factor (LF) enzyme secreted by Bacillus anthracis is a zinc hydrolase that is chiefly responsible for anthrax-related cell death. Although many studies of the design of small molecule LF inhibitors have been conducted, no LF inhibitor is yet available as a therapeutic agent. Inhibitors with considerable chemical diversity have been developed and investigated; however, the LF S2鈥?subsite has not yet been systematically explored as a potential target for lead optimization. Here we present synthesis, experimental evaluation, modeling, and structural biology for a novel series of sulfonamide hydroxamate LF inhibitor analogues specifically designed to extend into, and probe chemical preferences of, this S2鈥?subsite. We discovered that this region accommodates a wide variety of chemical functionalities and that a broad selection of ligand structural modifications directed to this area can be incorporated without significant deleterious alterations in biological activity. We also identified key residues in this subsite that can potentially be targeted to improve inhibitor binding.