- February 2017 (1)
- January 2017 (2)
- June 2016 (1)
- May 2016 (1)
- December 2015 (1)
- November 2015 (2)
- September 2015 (1)
- July 2015 (1)
- June 2015 (3)
- May 2015 (1)
- January 2015 (1)
- December 2014 (1)
- November 2014 (2)
- September 2014 (4)
- August 2014 (2)
- July 2014 (3)
- June 2014 (1)
- May 2014 (3)
- April 2014 (2)
- February 2014 (2)
- January 2014 (1)
- December 2013 (2)
- November 2013 (3)
- October 2013 (1)
- September 2013 (1)
- August 2013 (2)
- July 2013 (2)
- May 2013 (1)
- April 2013 (1)
- February 2013 (2)
- January 2013 (1)
- December 2012 (2)
- November 2012 (1)
- October 2012 (2)
- July 2012 (2)
- May 2012 (4)
- April 2012 (2)
- March 2012 (2)
- January 2012 (3)
- 3D7 IC50 Avery Lab (3)
- AstraZeneca (2)
- MetID (3)
- Potencies GSK (1)
- Potencies Guy (1)
- Syngene (8)
- UCSD (1)
- Biology (37)
- DMPK (2)
- Dundee (2)
- GSH-EE - Chapman Lab (2)
- GSK PRR Assay (1)
- Imperial DGFA (1)
- Kirk Lab (5)
- Metabolism (1)
Stephan Meister from Elizabeth Winzeler's laboratory at UCSD tested two Series 1 Compounds in a liver stage assay to provide some greater context for the first Open Source Malaria Paper.
The aryl pyrrole OSM-S-5 and near neighbour OSM-S-38 were both blood-stage active compounds from Series 1 and were both evaluated in this assay. OSM-S-5 showed an IC50 of 23 uM, whilst OSM-S-38 had an activity of 19 nM with no HepG2 cytotoxicity. These data may provide some evidence that these two series of compounds may have distinct mechanisms of action.
Previously OSM-S-111, another of the near neighbours (analogous to OSM-S-38) had shown moderate potency in the same assay:
Liver stage malaria activities of OSM-S-106 and OSM-S-111 in Plasmodium berghei.
Data:
General assay principle:
This assay is based on the murine Plasmodium berghei species transformed with Luciferase. Hepatic human transformed cells (HepG2), pretreated for two hours with the compound to investigate, are infected with freshly dissected P. berghei Luciferase sporozoites. After 48 hours of incubation with the compound to investigate, the viability of P. berghei exoerythrocytic forms (EEF) is measured by bioluminescence.
This assay allows us to identify compounds with an eventual activity against sporozoite infection of liver cell as well the viability of liver schizonts.
Update Sept 10th 2015
The compounds were re-tested by Stephan and Jenya Antonova, giving broadly similar results: OSM-S-5 showed an IC50 of 14 uM, whilst OSM-S-38 had an activity of 13 nM.
This raises the question of whether OSM-S-38 should be tested in the Pc liver stage assay at the BPRC in the Netherlands.
This post originally authored by Alice Williamson. Edited by Mat Todd. Updated with new data by Mat Todd.
SOP :
Parasites.
Plasmodium berghei Luciferase sporozoites were obtained by dissection of infected A. stephensi mosquito salivary glands supplied by the New York University Insectary. Dissected salivary glands were homogenized in a glass tissue grinder and filtered twice through Nylon cell strainers (40 μm pore size, BD Falcon) and counted using a hemocytometer. The sporozoites were kept on ice until needed.
Strings:
OSM-S-5: TCMDC-123812 CC(N1C2=CC=C(F)C=C2)=C(C(OCC(N)=O)=O)C=C1C InChI=1S/C15H15FN2O3/c1-9-7-13(15(20)21-8-14(17)19)10(2)18(9)12-5-3-11(16)4-6-12/h3-7H,8H2,1-2H3,(H2,17,19) YSUCFIZUNLQZDX-UHFFFAOYSA-N
OSM-S-38: CC1=CC(/C=C(C(N/2)=O)\SC2=N/C3=CC=CC=C3)=C(C)N1C(C=C4)=CC=C4C(F)(F)F InChI=1S/C23H18F3N3OS/c1-14-12-16(15(2)29(14)19-10-8-17(9-11-19)23(24,25)26)13-20-21(30)28-22(31-20)27-18-6-4-3-5-7-18/h3-13H,1-2H3,(H,27,28,30)/b20-13- YBBWTVGRVHTTDD-MOSHPQCFSA-N
OSM-S-111: O=C(/C(S/1)=C/C2=C(C)N(C3=CC=C(OC)C=C3)C(C)=C2)NC1=N\C4=CC=CC=C4 InChI=1S/C23H21N3O2S/c1-15-13-17(16(2)26(15)19-9-11-20(28-3)12-10-19)14-21-22(27)25-23(29-21)24-18-7-5-4-6-8-18/h4-14H,1-3H3,(H,24,25,27)/b21-14- KXIVXNPEYYNDHE-STZFKDTASA-N