The development of drugs to treat malaria has been slow, too slow in fact to keep pace with the quickly adapting parasite that has developed mechanisms of resistance against all current treatments.
Nature now features two articles that release screening results against Plasmodium falciparum, the malaria causing blood parasite. One comes from GlaxoSmithKline, the other from an academic and clinical consortium (Guy et al).
Guy et al have tested ~300.000 compounds and GSK have screened what I believe is their entire library of just about 2mio compounds against the laboratory malarial strain 3D7. Both assay systems are cell based and hence do not associate compounds with explicit protein targets.
GSK identifies 13,533 compounds as confirmed hits (with data deposited in ChEMBL) and Guy et al report dose-response curves for 1,134 validated hits. Guy et al go on cherry-picking 172 of their reported hits for cross validation against 66 Plasmodium proteins including the hemzoin-forming pathways, dehydroorotate dehydrogenase and falcipain. They analyze all results based on a tree that is constructed from compound similarities and looks very funky.
GSK keep it cheap but systematic and hypothesize about molecular targets based on a scheme that clusters compounds according to similarity and associates these clusters with targets that have been reported in previous assays for any compound in the cluster. Most of these targets are in fact human proteins and therefore the Plasmodium targets are inferred by sequence homology. The hypothesis that similar compounds bind the same target seems a bit naive but to be fair is likely to be the most practical approach to handle the very large number of reported hits.
One might get carried away comparing the different approaches of a pharmaceutical company and an academic consortium and project a few stereotypes but let's not do that! Both papers tell a story with open end, failing to comprehensively explore (and exploit) the set of reported hits. Cheer up, resolve is that they provide many opportunities for drug discovery!
Clearly there are limitations to the exploitability of this data as most of the reported interactions are on a cellular level with only a minority of compounds passed on to protein-level screens. Yet both papers rock as finally efforts are made to tackle malaria with structures deposited in open access databases.
Sunday, 23 May 2010
Sunday, 16 May 2010
Mechanism of action of arsenic trioxide
My boss, on a half-minute pit-stop in the data-integration office, uttered concern about the liberal use of the term 'ancient remedy' in a recent Science paper [1] that reports the mechanism of action of As2O3 in the treatment of acute promyelocytic leukemia (APL).
His complaint dumbfounded me, so strong was my conviction that As2O3 is used, if at all, to kill off parasites or for the poisoning of competing heirs in the Medici family.
However, already in the the seventies, chinese scientists at Harbin University tested a solution they had reproduced from a traditional recipe, Ai-Ling No.1, in cancer patients and in subsequent studies found that it was an effective treatment for APL [2]. In APL, a chromosomal translocation leads to the formation of PML-RARα, a fusion protein that contains a retinoic acid receptor domain and that prevents myeloid differentiation. In the nineties, the active ingredient of Ai-Ling No.1 was determined to be As2O3 [3] and the substance is now used in combination with retinoic acid to treat APL, FDA aproved at that. But even earlier, in the 19th century, the As2O3-containing Fowler's solution was reported to have cured a patient from acute leukemia by the Breslau physician Heinrich Lissauer [4].
As reported recently, the mechanism of action of As2O3 has recently been unravelled, the As2+ cation replaces Zn2+ in the zinc-finger domain of the RARα part of PML-RARα and induces a conformational change that leads to oligomerisation of the fusion protein. The aggregated proteins are ubiquitinated and SUMO-modified, which leads to their rapid degradation, allowing the dysfunctional myeloid precursor cell to differentiate normally.
Whether As2O3 can legitimately be called an ancient remedy remains questionable, after all traditional medicines are generally applied to a a wide and often diffuse spectrum of symptoms while APL is a very specific and rare form of blood cancer.
References:
[1] Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, Liang WX, Song AX, Lallemand-Breitenbach V, Jeanne M, Zhang QY, Yang HY, Huang QH, Zhou GB, Tong JH, Zhang Y, Wu JH, Hu HY, de Thé H, Chen SJ, Chen Z: Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 328(5975):240-3, 2010
[2] Zhang TD: Treatment of acute granulocytic leukemia with “Ai ling No. 1”: clinical analysis and experimental research. Chin J Comb Trad West Med 4:19-20, 1984
[3] Zhang P, Wang SY, Hu LH, et al: Treatment of acute promyelocytic leukemia with arsenic trioxide injection (“713”): Clinical observations and study of action mode. Chin J Hematol 17:58-60, 1996
[4] Zwei Fälle von Leucaemie. Berliner Klinische Wochenschrift, 2, 403–404, 1865
His complaint dumbfounded me, so strong was my conviction that As2O3 is used, if at all, to kill off parasites or for the poisoning of competing heirs in the Medici family.
However, already in the the seventies, chinese scientists at Harbin University tested a solution they had reproduced from a traditional recipe, Ai-Ling No.1, in cancer patients and in subsequent studies found that it was an effective treatment for APL [2]. In APL, a chromosomal translocation leads to the formation of PML-RARα, a fusion protein that contains a retinoic acid receptor domain and that prevents myeloid differentiation. In the nineties, the active ingredient of Ai-Ling No.1 was determined to be As2O3 [3] and the substance is now used in combination with retinoic acid to treat APL, FDA aproved at that. But even earlier, in the 19th century, the As2O3-containing Fowler's solution was reported to have cured a patient from acute leukemia by the Breslau physician Heinrich Lissauer [4].
As reported recently, the mechanism of action of As2O3 has recently been unravelled, the As2+ cation replaces Zn2+ in the zinc-finger domain of the RARα part of PML-RARα and induces a conformational change that leads to oligomerisation of the fusion protein. The aggregated proteins are ubiquitinated and SUMO-modified, which leads to their rapid degradation, allowing the dysfunctional myeloid precursor cell to differentiate normally.
Whether As2O3 can legitimately be called an ancient remedy remains questionable, after all traditional medicines are generally applied to a a wide and often diffuse spectrum of symptoms while APL is a very specific and rare form of blood cancer.
References:
[1] Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, Liang WX, Song AX, Lallemand-Breitenbach V, Jeanne M, Zhang QY, Yang HY, Huang QH, Zhou GB, Tong JH, Zhang Y, Wu JH, Hu HY, de Thé H, Chen SJ, Chen Z: Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 328(5975):240-3, 2010
[2] Zhang TD: Treatment of acute granulocytic leukemia with “Ai ling No. 1”: clinical analysis and experimental research. Chin J Comb Trad West Med 4:19-20, 1984
[3] Zhang P, Wang SY, Hu LH, et al: Treatment of acute promyelocytic leukemia with arsenic trioxide injection (“713”): Clinical observations and study of action mode. Chin J Hematol 17:58-60, 1996
[4] Zwei Fälle von Leucaemie. Berliner Klinische Wochenschrift, 2, 403–404, 1865
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