Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3

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.

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

10.1101/2021.06.18.448949 ◽

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.

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Multifunctional Ligands with Glycogen Synthase Kinase 3 Inhibitory Activity as a New Direction in Drug Research for Alzheimer’s Disease

Current Medicinal Chemistry ◽

10.2174/0929867327666200427100453 ◽

2020 ◽

Vol 27 ◽

Author(s):

Agnieszka Jankowska ◽

Grzegorz Satała ◽

Andrzej J. Bojarski ◽

Maciej Pawłowski ◽

Grażyna Chłoń-Rzepa

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Inhibitory Activity ◽

Glycogen Synthase ◽

Neuropsychiatric Symptoms ◽

New Drugs ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Multifunctional Ligands

: Alzheimer’s disease (AD) belongs to the most common forms of dementia that causes a progressive loss of brain cells and leads to memory impairment and decline of other thinking skills. There is yet no effective treatment for AD; hence, the search for new drugs that could improve memory and other cognitive functions is one of the hot research topics worldwide. Scientific efforts are also directed toward combating behavioral and psychological symptoms of dementia, which are an integral part of the disease. Several studies have indicated that glycogen synthase kinase 3 beta (GSK3β) plays a crucial role in the pathogenesis of AD. Moreover, GSK3β inhibition provided beneficial effects on memory improvement in multiple animal models of AD. The present review aimed to update the most recent reports on the discovery of novel multifunctional ligands with GSK3β inhibitory activity as potential drugs for the symptomatic and disease-modifying therapy of AD. Compounds with GSK3β inhibitory activity seem to be an effective pharmacological approach for treating the causes and symptoms of AD as they reduced neuroinflammation and pathological hallmarks in animal models of AD and provided relief from cognitive and neuropsychiatric symptoms. These compounds have the potential to be used as drugs for the treatment of AD, but their precise pharmacological, pharmacokinetic, toxicological, and clinical profiles need to be defined.

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