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Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions.

Drinkwater N, Vinh NB, Mistry SN, Bamert RS, Ruggeri C, Holleran JP, Loganathan S, Paiardini A, Charman SA, Powell AK, Avery VM, McGowan S, Scammells PJ
Eur J Med Chem 110 43-64 (2016)
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Cited: 18 times
EuropePMC logo PMID: 26807544

Abstract

Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics.

Reviews - 4zx3 mentioned but not cited (1)

  1. Marine Invertebrates: A Promissory Still Unexplored Source of Inhibitors of Biomedically Relevant Metallo Aminopeptidases Belonging to the M1 and M17 Families. Pascual Alonso I, Almeida García F, Valdés Tresanco ME, Arrebola Sánchez Y, Ojeda Del Sol D, Sánchez Ramírez B, Florent I, Schmitt M, Avilés FX. Mar Drugs 21 279 (2023)

Articles - 4zx3 mentioned but not cited (1)

  1. X-ray crystal structure and specificity of the Toxoplasma gondii ME49 TgAPN2. Marijanovic EM, Weronika Swiderska K, Andersen J, Aschenbrenner JC, Webb CT, Drag M, Drinkwater N, McGowan S. Biochem J 477 3819-3832 (2020)


Reviews citing this publication (4)

  1. M1 aminopeptidases as drug targets: broad applications or therapeutic niche? Drinkwater N, Lee J, Yang W, Malcolm TR, McGowan S. FEBS J 284 1473-1488 (2017)
  2. Proteases as antimalarial targets: strategies for genetic, chemical, and therapeutic validation. Deu E. FEBS J 284 2604-2628 (2017)
  3. Structural Insights Into Key Plasmodium Proteases as Therapeutic Drug Targets. Mishra M, Singh V, Singh S. Front Microbiol 10 394 (2019)
  4. Driving antimalarial design through understanding of target mechanism. Calic PPS, Mansouri M, Scammells PJ, McGowan S. Biochem Soc Trans 48 2067-2078 (2020)

Articles citing this publication (12)

  1. Design, synthesis, conformational and molecular docking study of some novel acyl hydrazone based molecular hybrids as antimalarial and antimicrobial agents. Kumar P, Kadyan K, Duhan M, Sindhu J, Singh V, Saharan BS. Chem Cent J 11 115 (2017)
  2. Biochemical and cellular characterisation of the Plasmodium falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP). Mathew R, Wunderlich J, Thivierge K, Cwiklinski K, Dumont C, Tilley L, Rohrbach P, Dalton JP. Sci Rep 11 2854 (2021)
  3. Mapping the Pathway and Dynamics of Bestatin Inhibition of the Plasmodium falciparum M1 Aminopeptidase PfA-M1. Yang W, Riley BT, Lei X, Porebski BT, Kass I, Buckle AM, McGowan S. ChemMedChem 13 2504-2513 (2018)
  4. An encryption-decryption framework to validating single-particle imaging. Shen Z, Teo CZW, Ayyer K, Loh ND. Sci Rep 11 971 (2021)
  5. Mapping the substrate specificity of the Plasmodium M1 and M17 aminopeptidases. Malcolm TR, Swiderska KW, Hayes BK, Webb CT, Drag M, Drinkwater N, McGowan S. Biochem J 478 2697-2713 (2021)
  6. N-Piperonyl substitution on aminoquinoline-pyrimidine hybrids: Effect on the antiplasmodial potency. Kholiya R, Khan SI, Bahuguna A, Tripathi M, Rawat DS. Eur J Med Chem 131 126-140 (2017)
  7. Novel Molecular Synapomorphies Demarcate Different Main Groups/Subgroups of Plasmodium and Piroplasmida Species Clarifying Their Evolutionary Relationships. Sharma R, Gupta RS. Genes (Basel) 10 E490 (2019)
  8. Two cap residues in the S1 subsite of a Plasmodium falciparum M1-family aminopeptidase promote broad specificity and enhance catalysis. Rosati M, Dalal S, Klemba M. Mol Biochem Parasitol 217 7-12 (2017)
  9. Generation of AMBER force field parameters for zinc centres of M1 and M17 family aminopeptidases. Yang W, Riley BT, Lei X, Porebski BT, Kass I, Buckle AM, McGowan S. J Biomol Struct Dyn 36 2595-2604 (2018)
  10. Active site metals mediate an oligomeric equilibrium in Plasmodium M17 aminopeptidases. Malcolm TR, Belousoff MJ, Venugopal H, Borg NA, Drinkwater N, Atkinson SC, McGowan S. J Biol Chem 296 100173 (2021)
  11. Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway. Edgar RCS, Siddiqui G, Hjerrild K, Malcolm TR, Vinh NB, Webb CT, Holmes C, MacRaild CA, Chernih HC, Suen WW, Counihan NA, Creek DJ, Scammells PJ, McGowan S, de Koning-Ward TF. Elife 11 e80813 (2022)
  12. Structural characterization of plasmodial aminopeptidase: a combined molecular docking and QSAR-based in silico approaches. Wang F, Hu X, Zhou B. Mol Divers 23 965-984 (2019)


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