2. Academic Validation
  3. Activity refinement of aryl amino acetamides that target the P. falciparum STAR-related lipid transfer 1 protein

Activity refinement of aryl amino acetamides that target the P. falciparum STAR-related lipid transfer 1 protein

  • Eur J Med Chem. 2024 Mar 25:270:116354. doi: 10.1016/j.ejmech.2024.116354.
William Nguyen 1,  Coralie Boulet 2,  Madeline G Dans 1,  Katie Loi 1,  Kate E Jarman 1,  Gabrielle M Watson 1,  Wai-Hong Tham 1,  Kate J Fairhurst 3,  Tomas Yeo 3,  David A Fidock 4,  Sergio Wittlin 5,  Mrittika Chowdury 6,  Tania F de Koning-Ward 6,  Gong Chen 7,  Dandan Yan 7,  Susan A Charman 7,  Delphine Baud 8,  Stephen Brand 8,  Paul F Jackson 9,  Alan F Cowman 1,  Paul R Gilson 2,  Brad E Sleebs 10
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • 2 Burnet Institute, Melbourne, Victoria, 3004, Australia.
  • 3 Department of Microbiology & Immunology, Columbia University, Irving Medical Center, New York, 10032, NY, USA.
  • 4 Department of Microbiology & Immunology, Columbia University, Irving Medical Center, New York, 10032, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University, Irving Medical Center, New York, 10032, NY, USA.
  • 5 Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwi, Switzerland; University of Basel, 4003, Basel, Switzerland.
  • 6 School of Medicine, Deakin University, Waurn Ponds, Victoria, 3216, Australia; Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Victoria, 3216, Australia.
  • 7 Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
  • 8 Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215, Geneva, Switzerland.
  • 9 Global Public Health, Janssen R&D LLC, La Jolla, 92121, USA.
  • 10 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia. Electronic address: sleebs@wehi.edu.au.
PMID: 38554474 DOI: 10.1016/j.ejmech.2024.116354
Abstract

Malaria is a devastating disease that causes significant morbidity worldwide. The development of new antimalarial chemotypes is urgently needed because of the emergence of resistance to frontline therapies. Independent phenotypic screening campaigns against the Plasmodium asexual Parasite, including our own, identified the aryl amino acetamide hit scaffold. In a prior study, we identified the STAR-related lipid transfer protein (PfSTART1) as the molecular target of this antimalarial chemotype. In this study, we combined structural elements from the different aryl acetamide hit subtypes and explored the structure-activity relationship. It was shown that the inclusion of an endocyclic nitrogen, to generate the tool compound WJM-715, improved aqueous solubility and modestly improved metabolic stability in rat hepatocytes. Metabolic stability in human liver microsomes remains a challenge for future development of the aryl acetamide class, which was underscored by modest systemic exposure and a short half-life in mice. The optimized aryl acetamide analogs were cross resistant to parasites with mutations in PfSTART1, but not to other drug-resistant mutations, and showed potent binding to recombinant PfSTART1 by biophysical analysis, further supporting PfSTART1 as the likely molecular target. The optimized aryl acetamide analogue, WJM-715 will be a useful tool for further investigating the druggability of PfSTART1 across the lifecycle of the malaria Parasite.

Keywords

Antimalarial; Aryl amino acetamide; Malaria; Plasmodium; STAR lipid transfer.

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