Development of inhibitors of <em>Plasmodium falciparum</em> apical membrane antigen 1 based on fragment screening — ASN Events
  1. Schedule
  2. Session 10: Poster Session C
  3. Development of inhibitors of Plasmodium falciparum apical membrane antigen 1 based on fragment screening

Development of inhibitors of Plasmodium falciparum apical membrane antigen 1 based on fragment screening (#348)

San Sui Lim 1 , Krishnarjuna Bankala 1 , Chris MacRaild 1 , Indu Chandrashekaran 1 , Hiromasa Yagi 1 , Cael Debono 1 , Shane Devine 1 , Jamie Simpson 1 , Robin Anders 2 , Martin Scanlon 1 , Peter Scammells 1 , Raymond Norton 1
  1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parville, Victoria, Australia
  2. Department of Biochemistry, La Trobe University, Bundoora, Victoria, Australia

Malaria is one of the most widespread infectious diseases, causing approximately 250 million clinical cases and claiming nearly a million lives each year. Although current artemisinin combination therapies (ACT) have been highly effective against Plasmodium parasites, signs of resistance have already emerged.1 Hence, there is an urgent need for drugs with new modes of action to combat this threat. Apical membrane antigen 1 (AMA1) is an essential component of the moving junction (MJ) used by Plasmodium merozoites to invade human red blood cells.2 AMA1 has a conserved hydrophobic cleft that is the site of key interactions with the rhoptry neck (RON) protein complex that forms part of the moving junction.3 Peptides identified by phage display, such as R1, as well as monoclonal antibodies that target this site on AMA1, are able to inhibit red blood cell invasion, but usually in a strain-specific manner as numerous polymorphic residues are clustered at one end of the cleft.

Our goal is to design small molecule inhibitors of AMA1 that have broad strain specificity, and we are pursuing this goal using a fragment-based approach.4 Our initial screening using saturation transfer difference (STD) and Carr-Purcell-Meiboom-Gill (CPMG) NMR spectroscopy, as well as surface plasmon resonance (SPR), have identified efficient binders that interact with the hydrophobic groove.5 The specific binding sites of these hits have been mapped using 1H-15N HSQC chemical shift perturbation studies of AMA1. Chemical modifications of these hits based on the structure-activity relationship of the analogues are currently underway to improve their binding affinities.             

  1. Duffy, P. E.; Sibley, C. H., The Lancet 2005, 366 (9501), 1908-1909.
  2. MacRaild, C. A.; Anders, R. F.; Foley, M.; Norton, R. S., Curr. Top. Med. Chem. 2011, 11 (16), 2039-2047.
  3. Richard, D.; MacRaild, C. A.; Riglar, D. T.; Chan, J.-A.; Foley, M.; Baum, J.; Ralph, S. A.; Norton, R. S.; Cowman, A. F., J. Biol. Chem. 2010, 285 (19), 14815-22.
  4. Hajduk, P.; Greer, J., Nat. Rev. Drug Discov. 2007, 6 (3), 211-219.
  5. Lim S. S.; Debono C. O.; MacRaild C. A.; Chandrashekaran, I. R.; Dolezal O.; Anders R. F.; Simpson J. S.; Scanlon, M. J.; Devine, S. M.; Scammells, P. J.; Norton, R. S.; Aust. J. Chem. 2013, in press