Probing the S2' Subsite of the Anthrax Toxin Lethal Factor Using Novel N-Alkylated Hydroxamates.
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' 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' 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.
Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55414, United States.
Elbek K
EK
Kurbanov
Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55414, United States.
Ting-Lan
TL
Chiu
Institute for Therapeutics Discovery and Development, University of Minnesota , Minneapolis, Minnesota 55414, United States.
Jonathan
J
Solberg
Institute for Therapeutics Discovery and Development, University of Minnesota , Minneapolis, Minnesota 55414, United States.
Subhashree
S
Francis
Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55414, United States.
Kimberly M
KM
Maize
Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55414, United States.
Jenna
J
Fernandez
Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55414, United States.
Rodney L
RL
Johnson
Institute for Therapeutics Discovery and Development, University of Minnesota , Minneapolis, Minnesota 55414, United States.
Jon E
JE
Hawkinson
Institute for Therapeutics Discovery and Development, University of Minnesota , Minneapolis, Minnesota 55414, United States.
Michael A
MA
Walters
Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55414, United States.
Barry C
BC
Finzel
Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55414, United States.|Minnesota Supercomputing Institute for Advanced Computational Research, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Elizabeth Ambrose
EA
Amin
D000478:Alkylation; D000881:Anthrax / Q000188:drug therapy / Q000382:microbiology*; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000378:metabolism; D001408:Bacillus anthracis / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C030325:anthrax toxin