Exploration of benzofuran-based compounds as potent and selective Plasmodium falciparum glycogen synthase kinase-3 (PfGSK-3) inhibitors

2021 ◽  
pp. 104839
Author(s):  
Chantalle Moolman ◽  
Rencia van der Sluis ◽  
Richard M. Beteck ◽  
Lesetja J. Legoabe
Keyword(s):  
Plasmodium Falciparum ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

scholarly journals N-terminal phosphorylation regulates the activity of Glycogen Synthase Kinase 3 from Plasmodium falciparum

2022 ◽  
Author(s):  
Samuel Pazicky ◽  
Arne Alder ◽  
Haydyn Mertens ◽  
Dmitri I. Svergun ◽  
Tim Gilberger ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Conformational Changes ◽  
Glycogen Synthase ◽  
New Drugs ◽  
Glycogen Synthase Kinase ◽  
Scattering Data ◽  
Glycogen Synthase Kinase 3 ◽  
X Ray ◽  
X Ray Scattering ◽  
Novel Targets

As the decline of malaria cases stalled over the last five years, novel targets in Plasmodium falciparum are necessary for the development of new drugs. Glycogen Synthase Kinase (PfGSK3) has been identified as a potential target, since its selective inhibitors were shown to disrupt the parasite's life cycle. In the uncanonical N‑terminal region of the parasite enzyme, we identified several autophosphorylation sites and probed their role in activity regulation of PfGSK3. By combining molecular modeling with experimental small-angle X-ray scattering data, we show that increased PfGSK3 activity is promoted by conformational changes in the PfGSK3 N‑terminus, triggered by N‑terminal phosphorylation. Our work provides novel insights into the structure and regulation of the malarial PfGSK3.

3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3

2012 ◽  
Vol 56 (1) ◽  
pp. 264-275 ◽  
Author(s):  
Wiebke Fugel ◽  
Anselm Erich Oberholzer ◽  
Bernhard Gschloessl ◽  
Ron Dzikowski ◽  
Narkiss Pressburger ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Selective Inhibitors

scholarly journals N-terminal phosphorylation regulates the activity of Glycogen Synthase Kinase 3 from Plasmodium falciparum

2021 ◽  
Author(s):  
Samuel Pazicky ◽  
Arne Alder ◽  
Haydyn Mertens ◽  
D. I. Svergun ◽  
Tim Gilberger ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Conformational Changes ◽  
Glycogen Synthase ◽  
New Drugs ◽  
Glycogen Synthase Kinase ◽  
Scattering Data ◽  
Glycogen Synthase Kinase 3 ◽  
X Ray ◽  
X Ray Scattering

As the decline of malaria cases stalled over the last five years, novel targets in Plasmodium falciparum are necessary for the development of new drugs. Glycogen Synthase Kinase (PfGSK3) has been identified as a potential target, since its selective inhibitors were shown to disrupt the parasite`s life cycle. Here, we show that PfGSK3 exhibits autophosphorylation, leading to an extensive phosphorylation both in vitro and in the parasite. In the uncanonical N-terminal region of the parasite enzyme, we identified several autophosphorylation sites that regulate the activity of PfGSK3. By combining molecular modeling with experimental small-angle X-ray scattering data, we show that increased PfGSK3 activity is promoted by conformational changes in the PfGSK3 N-terminus, triggered by N-terminal phosphorylation. Our work provides novel insights into the structure and regulation of the malarial PfGSK3.

Sign in / Sign up

Export Citation Format

Share Document