Development of Chemical Entities Endowed with Potent Fast-Killing Properties against Plasmodium falciparum Malaria Parasites.
Alexios N Matralis,Adnan Malik,Maria Penzo,Maria Penzo,Inmaculada Moreno,Maria Jesus Almela,Isabel Camino,Benigno Crespo,Anas Saadeddin,Sonja Ghidelli-Disse,Lourdes Rueda,Félix Calderón,Simon A. Osborne,Gerard Drewes,Markus Boesche,Elena Fernández-Álvaro,Jose Ignacio Martin Hernando,David A. Baker +17 more
TLDR
The medicinal chemistry efforts focused on a cGMP-dependent protein kinase (PKG) inhibitor scaffold are described, leading to the identification of novel chemical entities with very potent, similar to artemisinins, fast-killing potency against asexual blood stages that cause disease, and activity against gametocyte activation that is required for transmission.Abstract:
One of the attractive properties of artemisinins is their extremely fast-killing capability, quickly relieving malaria symptoms. Nevertheless, the unique benefits of these medicines are now compromised by the prolonged parasite clearance times and the increasing frequency of treatment failures, attributed to the increased tolerance of Plasmodium falciparum to artemisinin. This emerging artemisinin resistance threatens to undermine the effectiveness of antimalarial combination therapies. Herein, we describe the medicinal chemistry efforts focused on a cGMP-dependent protein kinase (PKG) inhibitor scaffold, leading to the identification of novel chemical entities with very potent, similar to artemisinins, fast-killing potency against asexual blood stages that cause disease, and activity against gametocyte activation that is required for transmission. Furthermore, we confirm that selective PKG inhibitors have a slow speed of kill, while chemoproteomic analysis suggests for the first time serine/arginine protein kinase 2 (SRPK2) targeting as a novel strategy for developing antimalarial compounds with extremely fast-killing properties.read more
Citations
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hERG toxicity assessment: Useful guidelines for drug design.
TL;DR: Clear guidelines are provided, based on described examples, illustrating successful optimization process to avoid hERG interactions as cases studies and to spur scientists to develop safe drugs.
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Plasmodium Kinases as Potential Drug Targets for Malaria: Challenges and Opportunities.
TL;DR: Key target attributes and experimental approaches are highlighted to consider and summarize the progress that has been made targeting Plasmodium PI4KIIIβ, cGMP-dependent protein kinase, and cyclin-dependent-like kinase 3 in malaria.
Journal ArticleDOI
Ca2+ signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG
Aurélia C. Balestra,Konstantinos Koussis,Natacha Klages,Steven Howell,Helen R. Flynn,Marcus Bantscheff,Carla Pasquarello,Abigail J. Perrin,Lorenzo Brusini,Patrizia Arboit,Olalla Sanz,Laura Peces-Barba Castaño,Chrislaine Withers-Martinez,Alexandre Hainard,Sonja Ghidelli-Disse,Ambrosius P. Snijders,David Baker,Michael J. Blackman,Michael J. Blackman,Mathieu Brochet +19 more
TL;DR: In this paper, the authors identify a multipass membrane protein, ICM1, with homology to transporters and calcium channels that is tightly associated with protein kinase (PKG) in both asexual blood stages and transmission stages.
Journal ArticleDOI
Targeting the Malaria Parasite cGMP-Dependent Protein Kinase to Develop New Drugs.
TL;DR: In this paper, the authors review previous work that has been carried out to develop and optimize inhibitors of the cGMP-dependent protein kinase (PKG) which is a critical regulator of the malaria parasite life cycle.
Journal ArticleDOI
Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments.
TL;DR: A systematic review of the literature highlights the strong potential of compounds targeting plasmodial kinases for future drug therapies, however, the majority of the Plasmodium kinome remains to be explored.
References
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Christopher S. Hughes,Sophia Foehr,David A. Garfield,Eileen E. M. Furlong,Lars M. Steinmetz,Jeroen Krijgsveld +5 more
TL;DR: A novel protocol using paramagnetic beads, termed Single‐Pot Solid‐Phase‐enhanced Sample Preparation (SP3), provides a rapid and unbiased means of proteomic sample preparation in a single tube that facilitates ultrasensitive analysis by outperforming existing protocols in terms of efficiency, scalability, speed, throughput, and flexibility.
Journal ArticleDOI
Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes
Marcus Bantscheff,Carsten Hopf,Mikhail M. Savitski,Antje Dittmann,Paola Grandi,Anne-Marie Michon,Judith Schlegl,Yann Abraham,Isabelle Becher,Giovanna Bergamini,Markus Boesche,Manja Delling,Birgit Dümpelfeld,Dirk Eberhard,Carola Huthmacher,Toby Mathieson,Daniel Poeckel,Valerie Reader,Katja Strunk,Gavain Sweetman,Ulrich Kruse,Gitte Neubauer,Nigel Ramsden,Gerard Drewes +23 more
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TL;DR: The data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites and imperils efforts to reduce the global malaria burden.
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