o*******a
发帖数: 242 | 1 Nature. 2015 Apr 30;520(7549):683-7. doi: 10.1038/nature14412. Epub 2015 Apr
15.
A molecular mechanism of artemisinin resistance in Plasmodium falciparum
malaria.
Mbengue A1, Bhattacharjee S1, Pandharkar T1, Liu H2, Estiu G2, Stahelin RV3,
Rizk SS1, Njimoh DL4, Ryan Y1, Chotivanich K5, Nguon C6, Ghorbal M7, Lopez-
Rubio JJ7, Pfrender M8, Emrich S9, Mohandas N10, Dondorp AM11, Wiest O12,
Haldar K1.
Abstract
Artemisinins are the cornerstone of anti-malarial drugs. Emergence and
spread of resistance to them raises risk of wiping out recent gains achieved
in reducing worldwide malaria burden and threatens future malaria control
and elimination on a global level. Genome-wide association studies (GWAS)
have revealed parasite genetic loci associated with artemisinin resistance.
However, there is no consensus on biochemical targets of artemisinin.
Whether and how these targets interact with genes identified by GWAS,
remains unknown. Here we provide biochemical and cellular evidence that
artemisinins are potent inhibitors of Plasmodium falciparum
phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of
action. In resistant clinical strains, increased PfPI3K was associated with
the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker
of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to
PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis
of PfPI3K and thus increased levels of the kinase, as well as its lipid
product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be
predictive of artemisinin resistance in both clinical and engineered
laboratory parasites as well as across non-isogenic strains. Elevated PI3P
induced artemisinin resistance in absence of PfKelch13 mutations, but
remained responsive to regulation by PfKelch13. Evidence is presented for
PI3P-dependent signalling in which transgenic expression of an additional
kinase confers resistance. Together these data present PI3P as the key
mediator of artemisinin resistance and the sole PfPI3K as an important
target for malaria elimination. | T*G
发帖数: 600 | 2 If this is true, other more potent PI3K inhibitors would have stronger
effects. Many companies tried to screen lead from house-hold or existing FDA
libraries, many of them contain PI3K inhibitors, without success. Hard to
believe this paper describes the true mechanism of arteminsinin
Apr
RV3,
Lopez-
【在 o*******a 的大作中提到】
: Nature. 2015 Apr 30;520(7549):683-7. doi: 10.1038/nature14412. Epub 2015 Apr
: 15.
: A molecular mechanism of artemisinin resistance in Plasmodium falciparum
: malaria.
: Mbengue A1, Bhattacharjee S1, Pandharkar T1, Liu H2, Estiu G2, Stahelin RV3,
: Rizk SS1, Njimoh DL4, Ryan Y1, Chotivanich K5, Nguon C6, Ghorbal M7, Lopez-
: Rubio JJ7, Pfrender M8, Emrich S9, Mohandas N10, Dondorp AM11, Wiest O12,
: Haldar K1.
: Abstract
: Artemisinins are the cornerstone of anti-malarial drugs. Emergence and
| r********r
发帖数: 109 | 3 Are they inhibitors for Plasmodium falciparum phosphatidylinositol-3-kinase
(PfPI3K) or human-PI3K?
FDA
【在 T*G 的大作中提到】
: If this is true, other more potent PI3K inhibitors would have stronger
: effects. Many companies tried to screen lead from house-hold or existing FDA
: libraries, many of them contain PI3K inhibitors, without success. Hard to
: believe this paper describes the true mechanism of arteminsinin
:
: Apr
: RV3,
: Lopez-
|
|
