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A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malariaMalaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug- resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.

Sci Transl Med. 2015 Jul 15;7(296):296ra111.
doi: 10.1126/scitranslmed.aaa6645.

The Science Publishing Group

©2015 American Association for the Advancement of Science.

  Phillips MA, ...et al..., Charman SA.

Another SBC Highlight:

Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892
Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892

To investigate the resistance mechanism attributed to ZbmA, the crystal structures of apo and Cu(II)-ZBM-bound ZbmA were determined.

Biochemistry. 2015 Nov 17;54(45):6842-51. doi: 10.1021/acs.biochem.5b01008. Epub 2015 Nov 5.

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Please Be Aware...!

 

APS requests the Experimental Safety Approval Form (ESAF) be submitted at least seven days prior to your scheduled beamtime.

 

Failure to submit your ESAF in advance may result in delaying the beginning of your experiment.

 

Future Meetings:

 

Biophysical Society Annual Meeting

February 27 - March 02, 2016

Los Angeles Convention Center; Los Angeles, CA

 

APS/CNM Users Meeting

May 09-12, 2016

Advanced Photon Source, Argonne National Laboratory; Argonne, IL

 

American Crystallographic Association, 2016

July 22-26, 2016

Downtown Sheraton Hotel; Denver CO

 

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SBC Beamtime Request System

The on-line SBC Beamtime Request System allows users to view available beamtime on 19-ID and 19-BM, and to submit a request for rapid beamtime allocation.

Beamtime is available to the research community via a peer reviewed proposal system; it is supported by the U.S. Department of Energy, Office of Biological and Environmental Research.

Current Beamline Statistics:

APS PDB Depositions from BioSync
SBC Sector 19 2013 2014 2015 TOTAL
ID BM ID BM ID BM
PDB Depositions 238 50 258 34 170 15 4618

APS Publications Database:

Publications Total
SBC-CAT Publication List: 19-ID 1352
SBC-CAT Publication List: 19-BM 507
SBC-CAT Publication List: ALL
APS Publications Database

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Beginning August 01, 2015 the Midwest Center for Structural Genomics (MCSG) will start accepting applications for access to the MCSG User Resource.

 

MCSG's structure determination platform is well established, and combines technologies, robotics and expertise for gene cloning, protein production, and crystallization, as well as biochemical and biophysical characterization.

 

For further information, please contact Andrzej Joachimiak.

 

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