2. Academic Validation
  3. Target fishing reveals PfPYK-1 and PfRab6 as potential targets of an antiplasmodial 4-anilino-2-trichloromethylquinazoline hit compound

Target fishing reveals PfPYK-1 and PfRab6 as potential targets of an antiplasmodial 4-anilino-2-trichloromethylquinazoline hit compound

  • Bioorg Med Chem. 2024 Mar 15:102:117654. doi: 10.1016/j.bmc.2024.117654.
C Kieffer 1,  N Primas 2,  S Hutter 3,  A Merckx 4,  L Reininger 5,  S Bach 5,  S Ruchaud 5,  F Gaillard 5,  M Laget 6,  D Amrane 7,  L Hervé 4,  C Castera-Ducros 2,  J Renault 8,  A Dumètre 3,  S Rault 1,  C Doerig 9,  P Rathelot 2,  P Vanelle 2,  N Azas 10,  P Verhaeghe 11
Affiliations

Affiliations

  • 1 Normandie Univ, UNICAEN, CERMN, 14000 Caen, France.
  • 2 Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Marseille, France; AP-HM, Service Central de la Qualité et de l'Information Pharmaceutiques, Hôpital Conception, Marseille 13005, France.
  • 3 Aix Marseille Univ, IHU Méditerranée Infection, UMR VITROME, IRD, SSA, Mycology & Tropical Eucaryotic Pathogens, Marseille, France.
  • 4 Université Paris Cité, MERIT, IRD, Paris, France.
  • 5 Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France; Sorbonne Université, CNRS, FR2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, 29680 Roscoff, France.
  • 6 Aix Marseille Univ, INSERMN, SSA, MCT, Marseille, France.
  • 7 Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Marseille, France.
  • 8 Université de Rennes - Faculté de Pharmacie, ISCR UMR CNRS 6226, Equipe CORINT, Rennes, France.
  • 9 School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
  • 10 Aix Marseille Univ, IHU Méditerranée Infection, UMR VITROME, IRD, SSA, Mycology & Tropical Eucaryotic Pathogens, Marseille, France. Electronic address: nadine.azas@univ-amu.fr.
  • 11 Univ. Grenoble Alpes, CNRS, DPM UMR 5063, F-38041 Grenoble, France; LCC-CNRS Université de Toulouse, CNRS, UPS, Toulouse, France; Service de Pharmacie, CHU de Nîmes, Place R. Debré, Nîmes, France. Electronic address: pierre.verhaeghe@univ-grenoble-alpes.fr.
PMID: 38452406 DOI: 10.1016/j.bmc.2024.117654
Abstract

We present investigations about the mechanism of action of a previously reported 4-anilino-2-trichloromethylquinazoline antiplasmodial hit-compound (Hit A), which did not share a common mechanism of action with established commercial antimalarials and presented a stage-specific effect on the erythrocytic cycle of P. falciparum at 8 < t < 16 h. The target of Hit A was searched by immobilising the molecule on a solid support via a linker and performing affinity chromatography on a plasmodial lysate. Several anchoring positions of the linker (6,7 and 3') and PEG-type linkers were assessed, to obtain a linked-hit molecule displaying in vitro antiplasmodial activity similar to that of unmodified Hit A. This allowed us to identify the PfPYK-1 kinase and the PfRab6 GTP-ase as potential targets of Hit A.

Keywords

2-trichloromethylquinazoline; Affinity chromatography; Antiplasmodial hit; Drug-linked matrix; PfPYK-1; PfRab6; Target fishing.

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